Hydroxamic and carboxylic acid derivatives

ABSTRACT

The subject invention concerns methods and compounds that have utility in the treatment of a condition associated with matrix metalloproteinase, ADAM or ADAM-TS enzymes, a condition that is mediated by TNF α or a condition involving a membrane-shedding event that is mediated by a metalloproteinase. Compounds of the invention are of formula I  
     (B) 2 N—X—(CH 2 ) m -W-(CR 1 R 2 ) n —COY  (I)  
     wherein  
     n=0 or 1;  
     m=0 or 1;  
     X is S(O) 1-2 ;  
     Y is OH or NHOH;  
     W is aryl or heteroaryl;  
     and the other groups are as defined herein.

FIELD OF THE INVENTION

[0001] This invention relates to hydroxamic and carboxylic acidderivatives, and to their use in medicine.

BACKGROUND TO THE INVENTION

[0002] Metalloproteinases, including matrix metalloproteinase (MMP),(human fibroblast) collagenase, gelatinase and TNFα convertase (TACE),and their modes of action, and also inhibitors thereof and theirclinical effects, are described in WO-A-96/11209, WO-A-97/12902 andWO-A-97/19075, the contents of which are incorporated herein byreference. MMP inhibitors may also be useful in the inhibition of othermammalian metalloproteinases such as the ADAM or ADAM-TS families.Members of the ADAM family include TNFα convertase (TACE) and ADAM-10,which can cause the release of TNFα from cells, and others, which havebeen demonstrated to be expressed by human articular cartilage cells andalso involved in the destruction of myelin basic protein, a phenomenonassociated with multiple sclerosis

[0003] Compounds which have the property of inhibiting the action ofmetalloproteinases involved in connective tissue breakdown, such ascollagenase, stromelysin and gelatinase, have been shown to inhibit therelease of TNFα both in vitro and in vivo. See Gearing et al (1994),Nature 370:555-557; McGeehan et al (1994), Nature 370:558-561;GB-A-2268934; and WO-A-93/20047. All of these reported inhibitorscontain a hydroxamic acid zinc-binding group, as do theimidazole-substituted compounds disclosed in WO-A-95/23790. Othercompounds that inhibit MMP and/or TNFα are described in WO-A-95/13289,WO-A-96/11209, WO-A-96/035687, WO-A-96/035711, WO-A-96/035712 andWO-A-96/035714.

[0004] WO-A-98/38859 discloses sulfonyl-divalent aryl/heteroarylhydroxamic compounds as MMP inhibitors. In addition to the claimedcompounds, it discloses related compounds includingN-hydroxy-2-[[4-(phenylmethyl)-1-piperidinyl]sulfonyl]benzamide, ashaving inferior properties.

[0005] Probenecid, i.e. 4-[(dipropylamino)sulfonyl]benzoic acid, haslong been known as a uricosuric agent; see U.S. Pat. No. 2,608,507.Certain metabolites are reported by Israeli et al, J. Med. Chem.15(7):709-13 (1972).

SUMMARY OF THE INVENTION

[0006] The invention encompasses novel compounds of formula (I) whichare useful inhibitors of matrix metalloproteinase, ADAM or ADAMTSenzymes, and which are useful for the treatment of diseases mediated bythose enzymes and/or TNFα mediated diseases, including degenerativediseases and certain cancers.

[0007] Novel compounds according to the invention are of the generaltype represented by formula (I):

(B)₂N—X—(CH₂)_(m)-W-(CR¹R²)_(n)—COY  (I)

[0008] wherein

[0009] n=0-1;

[0010] m=0-1;

[0011] X is S(O)₁₋₂;

[0012] Y is OH or NHOH;

[0013] W is aryl or heteroaryl;

[0014] R¹ is H, OR⁷ or a group (optionally substituted with R³) selectedfrom C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, C₁₋₆ alkyl-aryl,heteroaryl, C₁₋₆ alkyl-heteroaryl, cycloalkyl, C₁₋₆ alkyl-cycloalkyl,heterocycloalkyl, C₁₋₆ alkyl-heterocycloalkyl; and

[0015] R² is H or C₁₋₆ alkyl;

[0016] or CR¹R² is cycloalkyl or heterocycloalkyl optionally substitutedwith R³ or a group (optionally substituted with R³) selected from C₁₋₆alkyl, aryl, C₁₋₆ alkyl-aryl, heteroaryl, C₁₋₆ alkyl-heteroaryl;

[0017] R³ is OR⁷, COR⁷, CO₂R⁸, CON(R⁷)₂, N(R⁷)₂, NR⁷COR⁷, NR⁷CON(R⁷)₂,NR⁷CO₂R⁸, R⁷SO₂R⁸, S(O)₀₋₂R⁸, SO₂N(R⁷)₂ or cycloimidyl (optionallysubstituted with R⁴);

[0018] R⁴ is C₁₋₆ alkyl;

[0019] B is H or a group (optionally substituted with R⁵ or R⁶) selectedfrom C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, C₁₋₆ alkyl-aryl,heteroaryl, C₁₋₆ alkyl-heteroaryl, cycloalkyl, C₁₋₆ alkyl-cycloalkyl,heterocycloalkyl, C₁₋₆ alkyl-heterocycloalkyl, cycloalkenyl, andheterocycloalkenyl; and each instance of B may be the same or different;

[0020] R⁵ is a group (optionally substituted with R⁶) selected from C₁₋₆alkyl, aryl, C₁₋₆ alkyl-aryl, heteroaryl, C₁₋₆ alkyl-heteroaryl,cycloalkyl, C₁₋₆ alkyl-cycloalkyl, heterocycloalkyl and C₁₋₆alkyl-heterocycloalkyl;

[0021] or B-N-B is heterocycloalkyl optionally substituted with R⁵, R⁶,═O, or ═NOR⁵;

[0022] R⁶ is a group selected from N(R⁷)₂, NR⁷COR⁷, NR⁷CON(R⁷)₂,NR⁷CO₂R⁸, NR⁷SO₂R⁸, OR⁷, COR⁷, CO₂R⁴, CON(R⁷)₂, S(O)₀₋₂R⁸, andSO₂N(R⁷)₂;

[0023] R⁷ is H or a group selected from C₁₋₆ alkyl, aryl, C₁₋₆alkyl-aryl, heteroaryl, C₁₋₆ alkyl-heteroaryl, cycloalkyl, C₁₋₆alkyl-cycloalkyl, heterocycloalkyl and C₁₋₆ alkyl-heterocycloalkyl,wherein said group is optionally substituted with R⁸, COR⁸, SO₀₋₂R⁸,CO₂R⁸, OR⁸, CONR⁴R⁸, NR⁴R⁸, or SO₂NR⁴R⁸ and for each case of N(R⁷)₂ theR⁷ groups are the same or different or N(R⁷)₂ is heterocycloalkyloptionally substituted with R⁸, COR⁸, SO₀₋₂R⁸, CO₂R⁸, OR⁸, CONR⁴R⁸,NR⁴R⁸, or SO₂NR⁴R⁸;

[0024] R⁸ is C₁₋₆ alkyl, aryl, C₁₋₆ alkyl-aryl, heteroaryl or C₁₋₆alkyl-heteroaryl;

[0025] and the salts, solvates, hydrates, N-oxides, protected amino,protected carboxy and protected hydroxamic acid derivatives thereof.

[0026] Many compounds of formula I are new.

DESCRIPTION OF THE INVENTION

[0027] Preferred compounds of the invention are those wherein X is SO₂;Y is NHOH and/or B-N-B is optionally substituted heterocycloalkyl. Otherpreferences are defined in the subclaims.

[0028] It will be appreciated that the compounds according to theinvention can contain one or more asymmetrically substituted carbonatoms. The presence of one or more of these asymmetric centres in acompound of formula (I) can give rise to stereoisomers, and in each casethe invention is to be understood to extend to all such stereoisomers,including enantiomers and diastereomers, and mixtures including racemicmixtures thereof.

[0029] It will further be appreciated that the compounds according tothe invention may contain an oxime. This oxime can give rise togeometrical isomers, and in each case the invention is to be understoodto extend to all such isomers and mixtures thereof.

[0030] As used in this specification, alone or in combination, the term“C₁₋₆ alkyl” refers to straight or branched chain alkyl moiety havingfrom one to six carbon atoms, including or example, methyl, ethyl,propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl and the like.

[0031] The term “C₂₋₆ alkenyl” refers to a straight or branched chainalkyl moiety having two to six carbon atoms and having in addition onedouble bond, of either E or Z stereochemistry where applicable. Thisterm would include for example, vinyl, 1-propenyl, 1- and 2-butenyl,2-methyl-2-propenyl etc.

[0032] The term “C₂₋₆ alkynyl” refers to a straight or branched chainalkyl moiety having two to six carbon atoms and having in addition onetriple bond. This term would include for example, ethynyl, 1-propynyl,1- and 2-butynyl, 1-methyl-2-butynyl etc.

[0033] The term “cycloalkyl” refers to a saturated alicyclic moietyhaving from three to eight, e.g. 3-6, carbon atoms and includes, forexample, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl and bicyclo[2.2.1]heptanyl.

[0034] The term “cycloalkenyl” refers to an alicyclic moiety having fromthree to eight carbon atoms and having in addition one double bond. Thisterm includes, for example, cyclopentenyl, cyclooctenyl andbicyclo[2.2.1]heptenyl.

[0035] The term “heterocycloalkyl” refers to a saturated heterocyclicmoiety having from two to eight, e.g. 2-6, carbon atoms and one or moreheteroatom from the group N, O, S (or oxidised versions thereof) whichmay be optionally benzofused at any available position. This includes,for example, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl,benzodioxole and 8-oxabicyclo[3.2.1]octane.

[0036] The term “heterocycloalkenyl” refers to an alicyclic moietyhaving from three to eight carbon atoms and one or more heteroatomsselected from N, O, S and oxidised versions thereof, and having inaddition one double bond. This term includes, for example,dihydropyranyl and 8-oxabicyclo[3.2.1]octene.

[0037] The term “aryl” refers to an aromatic carbocyclic radical havinga single ring or two condensed rings, optionally substituted with anaryl group substituent. This term includes, for example, phenyl andnaphthyl.

[0038] The term “heteroaryl” refers to aromatic ring systems of five toten atoms of which at least one atom is selected from O, N and S, andoptionally substituted with an aryl group substituent. This termincludes, for example, furanyl, thiophenyl, pyridyl, indolyl andquinolyl.

[0039] The term “aryl group substituent” refers to a substituent chosenfrom halogen, CN, CF₃, CHF₂, CH₂F, OCF₃, OCHF₂, OCH₂F and NO₂. Thesubstituent may also be OC₁₋₆ alkyl.

[0040] The term “halogen” means fluorine, chlorine, bromine or iodine.

[0041] The term “benzofused” refers to the addition of a benzene ringsharing a common bond with the defined ring system.

[0042] The term “cycloimidyl” refers to a saturated ring of five to tenatoms containing the atom sequence —C(═O)NC(═O)—. The ring may beoptionally benzofused at any available position. Examples includesuccinimidoyl, phthalimidoyl and hydantoinyl.

[0043] The term “optionally substituted” means optionally susbstitutedwith one or more of the groups specified, at any available position orpositions.

[0044] The terms “protected amino”, “protected carboxy” and “protectedhydroxamic acid” mean amino, carboxy and hydroxamic acid groups whichcan be protected in a manner familiar to those skilled in the art. Forexample, an amino group can be protected by a benzyloxycarbonyl,tert-butoxycarbonyl, acetyl or like group, or may be in the form of aphthalimido or like group. A carboxyl group can be protected in the formof a readily-cleavable ester such as the methyl, ethyl, benzyl ortert-butyl ester. A hydroxamic acid may be protected as either N orO-substitued derivatives, such as O-benzyl or O-tert-butyldimethylsilyl.

[0045] Salts of compounds of formula (I) includepharmaceutically-acceptable salts, for example acid addition saltsderived from inorganic or organic acids, such as hydrochlorides,hydrobromides, p-toluenesulphonates, phosphates, sulphates,perchlorates, acetates, trifluoroacetates, propionates, citrates,malonates, succinates, lactates, oxalates, tartrates and benzoates.

[0046] Salts may also be formed with bases. Such salts include saltsderived from inorganic or organic bases, for example alkali metal saltssuch as magnesium or calcium salts, and organic amine salts such asmorpholine, piperidine, dimethylamine or diethylamine salts.

[0047] When the “protected carboxy” group in compounds of the inventionis an esterified carboxyl group, it may be a metabolically-labile esterof formula CO₂R⁹ where R⁹ may be an ethyl, benzyl, phenethyl,phenylpropyl, α or β-naphthyl, 2,4-dimethylphenyl, 4-tert-butylphenyl,2,2,2-trifluoroethyl, 1-(benzyloxy)benzyl, 1-(benzyloxy)ethyl,2-methyl-1-propionyloxypropyl, 2,4,6-trimethylbenzyloxymethyl orpivaloylmethyl group.

[0048] Compounds of the general formula (I) may be prepared by anysuitable method known in the art and/or by the following processes.

[0049] It will be appreciated that, where a particular stereoisomer offormula (I) is required, the synthetic processes described herein may beused with the appropriate homochiral starting material and/or isomersmaybe resolved from mixtures using conventional separation techniques(e.g. HPLC).

[0050] The compounds according to the invention may be prepared by thefollowing process. In the description and formulae below the groups R¹,R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, W, B, X and Y are as defined above,except where otherwise indicated. It will be appreciated that functionalgroups, such as amino, hydroxyl or carboxyl groups, present in thevarious compounds described below, and which it is desired to retain,may need to be in protected form before any reaction is initiated. Insuch instances, removal of the protecting group may be the final step ina particular reaction. Suitable protecting groups for such functionalitywill be apparent to those skilled in the art. For specific details seeGreene et al, “Protective Groups in Organic Synthesis”, WileyInterscience.

[0051] A process for preparing compounds of general formula (I)comprises acylating an amine of formula B₂NH (II) with an acylatingagent of formula Z—X—(CH₂)_(m)-W-(CR¹R²)_(n)—COY (III) wherein Zrepresents a suitable leaving group (e.g. a halogen such as chlorine),and Y is OH or NHOH or protected forms thereof such as OR¹⁰ (where R¹⁰is a suitable protecting group such as benzyl or tert-butyl) or NHOR¹¹(where R¹¹ is a suitable protecting group such as benzyl, tert-butyl ortert-butyldimethylsilyl).

[0052] Acylating agents of formula (III) where m=0 and X is SO₂, if notavailable commercially, may be prepared in a two-step process involvingthe sulfonation of an aromatic group of formula W-(CR¹R²)_(n)—COY (IV)to give a sulfonic acid HO—SO₂-W-(CR¹R²)_(n)—COY (V) followed byactivation to (III). Many compounds of formula (IV) are available, ormay be prepared by methods known to those skilled in the art.

[0053] Acylating agents of formula (III) where m=1 and X is SO₂ may beprepared from compounds of formula R¹²—S—CH₂-W-(CR¹R²)_(n)—COY (VI),where R¹² is H or a suitable labile group such as acetyl, by treatmentwith chlorine in an appropriate solvent such as water at an appropriatetemperature such as 0° C. Acylating agents of formula (III) where X═SOmay be prepared from compound (VI) by treatment with SO₂Cl₂ and aceticanhydride in an appropriate solvent such as dichloromethane at anappropriate temperature such as 0° C.

[0054] Sulfanyl compounds of formula (VI) may be prepared readily byalkylation of a compound R¹²SH with an alkylating agent of the formZ^(A)—CH₂-W-(CR¹R²)_(n)—COY (VII), where Z^(A) is a leaving group (e.g.a halogen such as bromine, or an alkylsulfonate ester such asmethanesulfonate). Many compounds of the form (VII) are availablecommercially, or may be prepared by standard chemistry known to thoseskilled in the art from materials available commercially.

[0055] Amines of the structure depicted in formula (II) are commerciallyavailable or may be prepared by standard aromatic, heteroaromatic orother chemistry known to those skilled in the art, from commerciallyavailable materials.

[0056] Compounds of formula (I) may also be prepared by interconversionof other compounds of formula (I). Thus, for example, compound offormula (I) where X═SO₂ may be prepared from a compound of formula (I)where X═SO by oxidation with, for example sodium periodate and rutheniumchloride trihydrate in an appropriate solvent, for exampleacetonitrile-tetrachloromethane-water. Hydroxamic acids (Y═NHOH) ofgeneral formula (I) may be prepared from carboxylic acids (Y═OH) offormula (I) using methods known to those skilled in the art.

[0057] Similarly, intermediates of any appropriate formula may beprepared by the interconversion of other compounds of the same formula.Thus, for example, a compound of formula (VI) where R² is not H may beprepared from a compound of formula (VI) where R² is H by reaction witha compound R²Z (where Z is as defined above) in the presence of a strongbase such as lithium diisopropylamide in an inert solvent such astetrahydrofuran.

[0058] Any mixtures of final products or intermediates obtained can beseparated on the basis of the physico-chemical differences of theconstituents, in known manner, into the pure final products orintermediates, for example by chromatography, distillation, fractionalcrystallization, or by formation of a salt if appropriate or possibleunder the circumstances.

[0059] The compounds according to the invention exhibit in vitroinhibiting activities with respect to the stromelysin, collagenase,gelatinase, ADAM or ADAM-TS enzymes. Compounds according to theinvention may also exhibit in vitro inhibition of membrane-sheddingevents known to be mediated by metalloproteinases, for example, α-APP,ACE, TGF-α, TNF-α, Fas ligand, selectins, TNFR-I, TNFR-II, CD30, II-6R,CD43, CD44, CD16-I, CD16-II, Folate receptor, CD23, or IL-1RII.

[0060] The activity and selectivity of the compounds may be determinedby use of the appropriate enzyme inhibition test, for example asdescribed in Examples A-M of WO-A-98/05635, by the assay for theinhibition of CD23 shedding described in WO-A-99/24399, or by thefollowing assay of TNF RI shedding.

[0061] The potency of the compounds of general formula (I) to act asinhibitors of the production of TNF RI is determined using the followingprocedure. A 100 μM solution of the inhibitor being tested or dilutionsthereof is incubated at 37° C. in an atmosphere of 5% CO₂ withperipheral blood mononuclear cells (PBMC). PBMC are isolated from buffycoats by standard procedures using Ficoll. A 100 μM solution of theinhibitor being tested or dilutions thereof is incubated for 22 hours at37° C. in an atmosphere of 5% CO₂ with 1×10⁶/ml PBMC stimulated withLPS. The cells are centrifuged down and the supernatant is assayed forTNF RI using a commercially available ELISA kit (R & D Systems). Theactivity in the presence of 0.1 mM inhibitor or dilutions thereof iscompared to activity in a control devoid of inhibitor and resultsreported as that inhibitor concentration effecting 50% inhibition of theproduction of TNF RI.

[0062] This invention also relates to a method of treatment for patients(including man and/or mammalian animals raised in the dairy, meat or furindustries or as pets) suffering from disorders or diseases which can beattributed to stromelysin as previously described, and morespecifically, a method of treatment involving the administration of thematrix metalloproteinase inhibitors of formula (I) as the activeconstituents.

[0063] Accordingly, the compounds of formula (I) can be used among otherthings in the treatment of osteoarthritis and rheumatoid arthritis, andin diseases and indications resulting from the over-expression of thesematrix metalloproteinases such as found in certain metastatic tumourcell lines.

[0064] As mentioned above, compounds of formula (I) are useful in humanor veterinary medicine since they are active as inhibitors of TNF andMMPs. Accordingly in another aspect, this invention concerns:

[0065] a method of management (by which is meant treatment ofprophylaxis) of disease or conditions mediated by TNF and/or MMPs inmammals, in particular in humans, which method comprises administeringto the mammal an effective, amount of a compound of formula (I) above,or a pharmaceutically acceptable salt thereof; and

[0066] a compound of formula (I) for use in human or veterinarymedicine, particularly in the management (by which is meant treatment orprophylaxis) of diseases or conditions mediated by TNF and/or MMPs; and

[0067] the use of a compound of formula (I) in the preparation of anagent for the management (by which is meant treatment or prophylaxis) ofdiseases or conditions mediated by TNF and/or MMPs.

[0068] The disease or conditions referred to above include inflammatorydiseases, autoimmune diseases, cancer, cardiovascular diseases, diseasesinvolving tissue breakdown such as rheumatoid arthritis, osteoarthritis,osteoporosis, neurodegeneration, Alzheimer's disease, stroke,vasculitis, Crohn's disease, ulcerative colitis, multiple sclerosis,periodontitis, gingivitis and those involving tissue breakdown such asbone resorption, haemorrhage, coagulation, acute phase response,cachexia and anorexia, acute infections, HIV infections, fever, shockstates, graft versus host reactions, dermatological conditions, surgicalwound healing, psoriasis, atopic dermatitis, epidermolysis bullosa,tumour growth, angiogenesis and invasion by secondary metastases,ophthalmological disease, retinopathy, corneal ulceration, reperfusioninjury, migraine, meningitis, asthma, rhinitis, allergic conjunctivitis,eczema, anaphylaxis, restenosis, congestive heart failure,endometriosis, atherosclerosis, endosclerosis and aspirin-independentanti-thrombosis.

[0069] Compounds of formula (I) may also be useful in the treatment ofpelvic inflammatory disease (PID), age-related macular degeneration andcancer-induced bone resorption Further, they can be used in thetreatment of lung diseases, e.g. selected from cystic fibrosis, adultrespiratory distress syndrome (ARDS), emphysema, bronchitisobliterans-organising pneumonia (BOOP), idiopathic pulmonary fibrosis(PIF), diffuse alveolar damage, pulmonary Langerhan's cellgranulamatosis, pulmonary lymphangioleiomyomatosis (LAM) and chronicobstructive pulmonary disease (COPD).

[0070] For the treatment of rheumatoid arthritis, osteoarthritis, and indiseases and indications resulting from the over-expression of matrixmetalloendoproteinases such as found in certain metastatic tumour celllines or other diseases mediated by the matrix metalloendoproteinases orincreased TNF production, the compounds of formula (I) may beadministered orally, topically, parenterally, by inhalation spray orrectally in dosage unit formulations containing non-toxicpharmaceutically acceptable carriers, adjuvants and vehicles. The termparenteral as used herein includes subcutaneous injections, intravenous,intramuscular, intrasternal injection or infusion techniques. Inaddition to the treatment of warm-blooded animals such as mice, rats,horses, cattle, sheep, dogs, cats etc, the compounds of the inventionare effective in the treatment of humans.

[0071] The pharmaceutical composition containing the active ingredientmay be in a form suitable for oral use, for example, as tablets,troches, lozenges, aqueous or oily suspensions, dispersible powders orgranules, emulsions, hard or soft capsules, or syrups or elixirs.Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavouringagents, colouring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients which are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in the gastointestinaltract and thereby provide a sustained action over a longer period. Forexample, a time delay material such as glyceryl monostearate or glyceryldistearate may be employed. They may also be coated by the techniquesdescribed in the U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874, toform osmotic therapeutic tablets for control release.

[0072] Formulations for oral use may also be presented as hard gelatincapsules where in the active ingredient is mixed with an inert soliddiluent, for example calcium carbonate, calcium phosphate or kaolin, oras soft gelatin capsules wherein the active ingredient is mixed withwater or an oil medium, for example peanut oil, liquid paraffin or oliveoil.

[0073] Aqueous suspensions contain the active materials in admixturewith excipients suitable for the manufacture of aqueous suspensions.Such excipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose,sodium alginate polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such a polyoxyethylene with partial esters derived from fattyacids and hexitol anhydrides, for example polyoxyethylene sorbitanmonooleate. The aqueous suspensions may also contain one or morepreservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one ormore colouring agents, one or more flavouring agents, and one or moresweetening agents, such as sucrose or saccharin.

[0074] Oily suspensions may be formulated by suspending the activeingredient in a vegetable oil, for example arachis oil, olive oil,sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.The oily suspensions may contain a thickening agent, for examplebeeswax, hard paraffin or cetyl alcohol. Sweetening agents such as thoseset forth above, and flavouring agents may be added to provide apalatable oral preparation. These compositions may be preserved by theaddition of an anti-oxidant such as ascorbic acid.

[0075] Dispersible powders and granules suitable for preparation of anaqueous suspension by the addition of water provide the activeingredient in admixture with a dispersing or wetting agent, suspendingagent and one or more preservatives. Suitable dispersing or wettingagents and suspending agents are exemplified, for example sweetening,flavouring and colouring agents may also be present.

[0076] The pharmaceutical compositions of the invention may also be inthe form of oil-in-water emulsions. The oily phase may be a vegetableoil, for example olive oil or arachis oil, or a mineral oil, for exampleliquid paraffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soya bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate and condensation products ofthe said partial esters with ethylene oxide, for example polyoxyethylenesorbitan monooleate. The emulsions may also contain sweetening andflavouring agents.

[0077] Syrups and elixirs may, be formulated with sweetening agents, forexample glycerol, propylene glycol, sorbitol or sucrose. Suchformulations may also contain a demulcent, a preservative and flavouringand colouring agents. The pharmaceutical compositions may be in the formof a sterile injectable aqueous or oleagenous suspension. Thissuspension may be formulated according to the known art using thosesuitable dispersing or wetting agents and suspending agents which havebeen mentioned above. The sterile injectable preparation may also be ina sterile injectable solution or suspension in a non-toxicparenterally-acceptable diluent or solvent, for example as a solution in1,3-butane diol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose any bland fixed oilmay be employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectables.

[0078] The compounds of formula (I) may also be administered in the formof suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

[0079] For topical use, creams, ointments, jellies, solutions orsuspensions, etc containing the compounds of Formula (I) are employed.For the purposes of this specification, topical application includesmouthwashes and gargles.

[0080] Dosage levels of the order of from about 0.05 mg to about 140 mgper kilogram of body weight per day are useful in the treatment of theabove-indicated conditions (about 2.5 mg to about 7 g per patient perday). For example, inflammation may be effectively treated by theadministration of from about 0.01 to 50 mg of the compound per kilogramof body weight per day (about 0.5 mg to about 3.5 g per patient perday).

[0081] The amount of active ingredient that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration. Forexample, a formulation intended for the oral administration of humansmay vary from about 5 to about 95% of the total composition. Dosage unitforms will generally contain between from about 1 mg to about 500 mg ofactive ingredient.

[0082] It will be understood, however, that the specific dose level forany particular patient will depend upon a variety of factors includingthe activity of the specific compound employed, the age, body weight,general health, sex, diet time of administration, route ofadministration, rate of excretion, drug combination and the severity ofthe particular disease undergoing therapy.

[0083] The following Examples illustrate compounds of the invention.

Intermediate 1 4-(4-Hydroxyphenyl)piperazine-1-carboxylic acidtert-butyl ester

[0084] To a stirred solution of 1-(4-hydroxyphenyl)piperazine (25 g) indichloromethane (150 ml) at 0° C. was added a solution of di-tert-butyldicarbonate (36.7 g) in dichloromethane (50 ml) dropwise. Stirring wascontinued for 30 mins at this temperature and then stirred at RT for afurther 24 h. The reaction mixture was washed with 10% aqueous citricacid (3×50 ml), saturated aqueous sodium hydrogen carbonate solution(3×50 ml), water (3×50 ml) and brine (50 ml). The organic layer was thendried (Na₂SO₄), filtered and the solvent removed under reduced pressureto give the title compound (33.9 g, 87%) as a brown solid.

[0085] R_(f) 0.13 (1:1 diethyl ether/hexane);

[0086] MS 278 (M⁺).

Intermediate 2 4-(4-Difluoromethoxyphenyl)piperazine-1-carboxylic acidtert-butyl ester

[0087] To a stirred solution of Intermediate 1 (2.0 g) in 1,4-dioxan (50ml) at 100° C. was added a solution of sodium hydroxide (0.86 g) inwater (5 ml). Through this mixture was bubbled chlorodifluoromethane for15 mins at this temperature before being allowed to cool to RT. Thesolvent was removed under reduced pressure and resulting residue waspartitioned between diethyl ether (100 ml) and water (50 ml). Theorganic layer collected and further washed with saturated aqueous sodiumhydrogencarbonate solution (3×50 ml), water (3×50 ml) and brine (50 ml).The organic layer was then dried (Na₂SO₄), filtered and the solventremoved under reduced pressure to give the title compound (1.44 g, 61%)as a beige solid.

[0088] R_(f) 0.51 (1:1 diethyl ether/hexane);

[0089] MS 329 (MH⁺).

Intermediate 3 1-(4-Difluoromethoxyphenyl)piperazine dihydrochloride

[0090] To a stirred solution of Intermediate 2 (1 4 g) indichloromethane (10 ml) at 0° C. was added a solution of trifluoroaceticacid (5 ml) in dichloromethane (5 ml). Stirring was continued for 30mins at this temperature and then stirred at RT for a further 2 h. Thesolvent was removed under reduced pressure and the resulting residueazeotroped with 1:1 hexane/dichloromethane (3×20 ml). Treatment of thismaterial with a solution of hydrogen chloride in diethyl ether (1.0M, 20ml) gave a suspension, which was subsequently collected by filtration.The precipitation was washed further with diethyl ether (3×20 ml) anddried under reduced pressure to give the title compound (0.74 g, 76%).

[0091] R_(f) 0.15 (ethyl acetate);

[0092] MS 229 (MH⁺+).

Intermediate 4 2-(Bromomethyl)benzoic acid methyl ester

[0093] Prepared as described by Dhanoa, J. Med. Chem., 36, 4230, (1993).

[0094] R_(f) 0.44 (5:1 hexane/diethyl ether);

[0095] MS 229 (M⁺).

Intermediate 5 2-(Cyanomethyl)benzenesulfonyl chloride

[0096] Prepared as described by Sianesi et al, Chem. Ber., 103,1992-2002, (1970).

[0097] R_(f) 0.60 (1:1 hexane/ethyl acetate);

[0098] MS 216 (M⁺).

Intermediate 6 (3a,7a-Dihydrobenzofuran-2-ylmethyl)methylamine

[0099] To a stirred solution of benzofuran-2-carboxaldehyde (1.50 g) and4 Å molecular sieves in dichloroethane (50 ml) under an atmosphere ofnitrogen was added methylamine in THF (2.0M, 10.3 ml) and acetic acid(1.23 g). Stirring was continued for 2 h before sodiumtriacetoxyborohydride (2.18 g) was added and stirring as continuedovernight. The mixture was filtered, absorbed onto silica gel andchromatographed eluting with dichloromethane/methanol (9:1) to yield thetitle compound (1.05 g, 64%) as an off-white solid.

[0100] R_(f) 0.30 (9:1 dichloromethane/methanol);

[0101] MS 229 (M⁺).

Intermediate 7 2-[4-(4-Chlorophenyl)piperazine-1-sulfonyl]benzoic acidmethyl ester

[0102] To stirred suspension of 4-(4-chlorophenyl)piperazinedihydrochloride (3.0 g) in dichloromethane (100 ml) at 0° C. was addedtriethylamine (4.6 ml). After 15 mins, a solution of2-chlorosulfonylbenzoic acid methyl ester (2.90 g) in dichloromethane(30 ml) was added. Stirring was continued overnight with the temperaturerising to RT. The reaction mixture was diluted with dichloromethane (100ml) and then washed with 10% aqueous citric acid (3×50 ml), saturatedaqueous sodium hydrogen carbonate solution (3×50 ml), water (3×50 ml)and brine (50 ml). The organic layer was then dried (MgSO₄), filteredand the solvent removed under reduced pressure to give the titlecompound (0.24 g, 48%) as an off-white solid.

[0103] R_(f) 0.57 (1:1 hexane/ethyl acetate);

[0104] MS 395 (MH⁺).

[0105] Similarly prepared were:

Intermediate 8 2-[4-(4-Chlorophenoxy)piperidine-1-sulfonyl]benzoic acidmethyl ester

[0106] From 2-chlorosulfonylbenzoic acid methyl ester (587 mg) and4-(4-chlorophenoxypiperidine (577 mg) as a brown oil (0.83 g, 97%).

[0107] R_(f) 0.53 (1:1 diethyl ether/hexane);

[0108] MS 410.6 (MH⁺).

Intermediate 92-[4-(4-Difluoromethoxyphenyl)piperazine-1-sulfonyl]benzoic acid methylester

[0109] From 2-chlorosulfonylbenzoic acid methyl ester (587 mg) andIntermediate 3 (602 mg) as a brown oil, (0.85 g, 99%).

[0110] R_(f) 0.44 (1:1 diethyl ether/hexane);

[0111] MS 426 (M⁺).

Intermediate 10 2-[4-(3,5-Dichlorophenyl)piperazine-1-sulfonyl]benzoicacid methyl ester

[0112] From 2-chlorosulfonylbenzoic acid methyl ester (587 mg) and4-(3,5-dichlorophenyl)piperazine (462 mg) as a green solid (0.76 g,89%).

[0113] R_(f)0.58 (1:1 diethyl ether/hexane);

[0114] MS 429 (M⁺).

Intermediate 112-[4-(4-Trifluoromethylpyridin-2-yl)piperazine-1-sulfonyl]benzoic acidmethyl ester

[0115] From 2-chlorosulfonylbenzoic acid methyl ester (587 mg) and4-(4-trifluoromethylpyridin-2-yl)piperidine (462 mg) as a brown oil(0.83 g, 96%).

[0116] R_(f) 0.62 (ethyl acetate);

[0117] MS 429 (M⁺).

Intermediate 12 2-[4-(4-Chlorobenzoyl)piperidine-1-sulfonyl]benzoic acidmethyl ester

[0118] From 2-chlorosulfonylbenzoic acid methyl ester (0.25 g) and4-(4-chlorobenzoyl)piperidine (221 mg) as a yellow oil (0.28 g, 78%).

[0119] R_(f) 0.55 (1:1 diethyl ether/hexane);

[0120] MS 422.6 (MH⁺).

Intermediate 13 2-(4-Benzylpiperidine-1-sulfonyl)benzoic acid methylester

[0121] From 2-chlorosulfonylbenzoic acid methyl ester (587 mg) and4-benzyl-piperidine (350 mg) as a brown oil (652 mg, 87%).

[0122] R_(f) 0.35 (1:1 diethyl ether/hexane);

[0123] MS 373 (M⁺).

Intermediate 14 2-[(4-Methoxyphenyl)methyl-sulfamoyl]benzoic acid methylester

[0124] From 2-chlorosulfonylbenzoic acid methyl ester (587 mg) andN-(4-methoxyphenyl)-methylamine (0.27 g) as a brown oil (0.53 g, 79%).

[0125] R_(f) 0.3 (1:1 diethyl ether/hexane);

[0126] MS 335 (M⁺).

Intermediate 15 2-[4-(Pyridin-2-yl)piperazine-1-sulfonyl]benzoic acidmethyl ester

[0127] From 2-chlorosulfonylbenzoic acid methyl ester (469 mg) and1-pyridin-2-yl-piperazine (408 mg) as a yellow oil (0.63 g, 87%).

[0128] R_(f) 0.35 (1:1 diethyl ether/hexane);

[0129] MS 361 (M⁺).

Intermediate 16 2-(3,4-Dihydro-1H-isoquinoline-2-sulfonyl)benzoic acidmethyl ester

[0130] From 2-chlorosulfonylbenzoic acid methyl ester (469 mg) and1,2,3,4-tetrahydro-isoquinoline (333 mg) as a yellow oil (475 mg, 71%).

[0131] R_(f) 0.25 (1:1 diethyl ether/hexane);

[0132] MS 331 (M⁺)

Intermediate 17 2-(Acetylsulfanylmethyl)benzoic acid methyl ester

[0133] To a stirred solution of Intermediate 4 (2.92 g) in DMF (5 ml) at0° C. was added potassium thioacetate (1.60 g). Stirring was continuedfor 30 mins at this temperature and then stirred at RT for a further 1h. The mixture was poured into ice/water (100 ml) and extracted withdiethyl ether (3×50 ml). The resulting ethereal extracted was furtherwashed with saturated aqueous sodium hydrogen carbonate solution (50ml), water (50 ml) and brine (50 ml). The organic layer was then dried(Na₂SO₄), filtered and the solvent removed under reduced pressure togive a brown oil. Purification by silica gel column chromatography,eluting with 5:1 hexane/diethyl ether gave the title compound (2.05 g,75%) as a colourless oil which subsequently solidified.

[0134] R_(f) 0.25 (5:1 hexane/diethyl ether);

[0135] MS 247 ([M+Na]⁺).

Intermediate 18 2-(Chlorosulfonylmethyl)benzoic acid methyl ester

[0136] To a stirred solution of Intermediate 17 (2 g) in glacial aceticacid (1 ml) at 5° C. was added water (100 ml). Through this suspensionwas bubbled chlorine gas for 20 minutes until a finely divided greensuspension developed. Addition of gas was stopped and stirring continuedfor 30 mins before dichloromethane (150 ml) was added. The organic wasthen collected and washed with saturated aqueous sodium hydrogencarbonate solution (50 ml), water (50 ml) and brine (50 ml). Theresulting extracts were dried (Na₂SO₄) and the solvent removed underreduced pressure to give the title compound (0.95 g, 85%) as a whitesolid.

[0137] R_(f) 0.48 (5:1 hexane/diethyl ether).

Intermediate 19 2-[4-(4-Chlorophenyl)piperazine-1-sulfonylmethyl]benzoicacid methyl ester

[0138] To stirred suspension of 4-(4-chlorophenyl)piperazinedihydrochloride (1.1 g) in dichloromethane (10 ml) at 0° C. was addedtriethylamine (2 ml). After 15 mins, a solution of Intermediate 18 (0.49g) in dichloromethane (5 ml) was added. Stirring was continued at thistemperature for 30 mins and then at RT for 1 hr. The reaction mixturewas diluted with dichloromethane (100 ml) and then washed with aqueous10% citric acid (3×50 ml), saturated aqueous sodium hydrogen carbonatesolution (3×50 ml), water (3×50 ml) and brine (50 ml). The organic layerwas then dried (Na₂SO₄), filtered and the solvent removed under reducedpressure to give the title compound (0.24 g, 48%) as a yellow oil.

[0139] R_(f) 0.55 (1:1 hexane/diethyl ether);

[0140] MS 409.5 (MH⁺).

[0141] Similarly prepared were:

Intermediate 202-[4-(4-Chlorophenoxy)piperidine-1-sulfonylmethyl]benzoic acid methylester

[0142] From Intermediate 18 (621 mg) and 4-(4-chlorophenoxy)piperidine(524 mg) as a yellow oil (0.16 g, 18%).

[0143] R_(f) 0.36 (1:1 diethyl ether/hexane);

[0144] MS 423.5 (MH⁺).

Intermediate 212-[4-(4-Chlorobenzoyl)piperidine-1-sulfonylmethyl]benzoic acid methylester

[0145] From Intermediate 18 (621 mg) and 4-(4-chlorobenzoyl)piperidine(520 mg) as a yellow oil (0.05 g, 6%).

[0146] R_(f) 0.39 (1:1 diethyl ether/hexane).

Intermediate 22 2-(3,4-Dihydro-1-H-isoquinoline-2-sulfonylmethyl)benzoicacid methyl ester

[0147] From Intermediate 18 (621 mg) and 3,4-dihydro-1-H-isoquinoline(266 mg) as a colourless oil (0.05 g, 7%).

[0148] R_(f) 0.38 (1:1 diethyl ether/hexane);

[0149] MS 346 (MH⁺).

Intermediate 232-[(Benzofuran-2-ylmethyl-methyl-sulfamoyl)methyl]benzoic acid methylester

[0150] From Intermediate 18 (0.45 g) and Intermediate 6 (0.30 g) as ayellow oil (0.23 g, 34%).

[0151] R_(f) 0.16 (1:1 diethyl ether/hexane);

[0152] MS 373 (M⁺).

Intermediate 24 2-[4-(Pyridin-2-yl)piperazine-1-sulfonylmethyl)benzoicacid methyl ester

[0153] From Intermediate 18 (0.50 g) and 1-(pyridin-2-yl)piperazine (408mg) as a beige solid (628 mg, 66%).

[0154] R_(f) 0.21 (1:1 diethyl ether/hexane);

[0155] MS 375 (M⁺).

Intermediate 252-[4-[5-(Trifluoromethyl)pyridin-2-yl]piperazine-1-sulfonylmethyl]benzoicacid methyl ester

[0156] From Intermediate 18 (0.50 g) and (5-trifluoromethylpyridin-2-yl)piperazine as a beige solid (712 mg, 65%).

[0157] R_(f) 0.13 (1:1 diethyl ether/hexane);

[0158] MS 443 (M⁺).

Intermediate 262-{4-[4-(1,1-Difluoromethoxy)phenyl]piperazine-1-sulfonylmethyl}benzoicacid methyl ester

[0159] From Intermediate 18 (0.3 g) and Intermediate 3 (0.451 g) as abeige solid (369 mg, 79%).

[0160] R_(f) 0.5 (diethyl ether);

[0161] MS 440 (M⁺).

Intermediate 27 2-{[(4-Methoxyphenyl)methylsulfamoyl]methyl}benzoic acidmethyl ester

[0162] From Intermediate 18 (0.5 g) and 4-methoxyphenyl-N-methylamine(278 mg) as a brown oil (479 mg, 62%).

[0163] R_(f) 0.57 (1:1 diethyl ether/hexane);

[0164] MS 350 (M⁺).

Intermediate 28{2-[4-(4-Chlorophenyl)piperazine-1-sulfonyl]phenyl}acetonitrile

[0165] To stirred suspension of 4-(4-chlorophenyl)piperazinedihydrochloride (400 mg) in dichloromethane (25 ml) at RT was addedtriethylamine (0.78 ml). After 15 mins, a solution of Intermediate 5(500 mg) in dichloromethane (5 ml) was added. Stirring was continued for2 h. The reaction mixture was diluted with dichloromethane (50 ml) andthen washed with aqueous citric acid (10%, 2×20 ml), saturated aqueoussodium hydrogen carbonate solution (2×20 ml), water (2×20 ml) and brine(20 ml). lime organic layer was then dried (MgSO₄), filtered and thesolvent removed under reduced pressure. The residue was chromatographed(2:1 hexane/ethyl acetate) to give the title compound (0.43 g, 61%) asan off-white solid.

[0166] R_(f) 0.37 (2:1 hexane/ethyl acetate).

[0167] Similarly prepared were:

Intermediate 292-Cyanomethyl-N-(4-methoxyphenyl)-N-methylbenzenesulfonamide

[0168] From Intermediate 5 (431 mg) and N-(4-methoxyphenyl)methylamine(274 mg) as an off-white solid (135 mg, 37%).

[0169] R_(f) 0.23 (2:1 hexane/ethyl acetate);

[0170] MS 317 (MH⁺).

Intermediate 30{2-[4-(4-Difluoromethoxyphenyl)piperazine-1-sulfonyl]phenyl}-acetonitrile

[0171] From Intermediate 3 (431 mg) and1-(4-difluoromethoxyphenyl)piperazine (456 mg) as a white solid (540 mg,66%).

[0172] R_(f) 0.24 (2:1 hexane/ethyl acetate);

[0173] MS 407 (MH⁺).

Intermediate 31{2-[4-(5-Trifluoromethylpyridin-2-yl)piperazine-1-sulfonyl]phenyl}acetonitrile

[0174] From Intermediate 11 (433 mg) and1-[5-(trifluoromethyl)pyrid-2-yl]piperazine (462 mg) as a white solid(683 mg, 83%).

[0175] R_(f) 0.37 (2:1 hexane/ethyl acetate);

[0176] MS 410 (MH⁺).

Intermediate 322-{2-[4-(4-Chlorophenyl)piperazine-1-sulfonyl]phenyl}-3-methyl-butyronitrile

[0177] Sodium hydride (43 mg of a 60% dispersion in oil) was added to asolution of Intermediate 28 (400 mg) in THF (20 ml). After stirring for5 min, isopropyl iodide (271 mg) was added. The mixture was stirred atroom temperature for 5 min and then at reflux for 30 min. It was cooledto room temperature and diluted with water (30 ml) before beingextracted with ethyl acetate (3×30 ml). The combined extracts werewashed with water (2×20 ml) and brine (20 ml), then dried (MgSO₄),evaporated and chromatographed (4:1 hexane/ethyl acetate) to give thetitle compound (235 mg, 53%) as a white foam.

[0178] R_(f) 0.42 (3:1 hexane:diethyl ether);

[0179] MS 417 (MH⁺).

EXAMPLE 1 2-[4-(4-Chlorophenyl)piperazine-1-sulfonyl]benzoic acid

[0180] To a stirred solution of Intermediate 7 (2.00 g) in a mixture ofmethanol (50 ml) and THF (30 ml) was added a solution of lithiumhydroxide monohydrate (1.06 g) in water (20 ml). The resultingsuspension was heated to reflux for 2 h. On cooling the solvent wasremoved under reduced pressure and the resulting residue partitionedbetween diethyl ether (50 ml) and water (100 ml). The aqueous layer wascollected and acidified to pH 5 with citric acid. The aqueous mixturewas then extracted with ethyl acetate (4×50 ml) and the combined organiclayers washed with water (40 ml) and brine (40 ml). Following drying(Na₂SO₄), the solvent was removed under reduced pressure to give thetitle compound (1.48 mg, 77%) as an off-white solid.

[0181] R_(f) 0.12 (1:1 hexane:diethyl ether);

[0182] MS 381 (MH⁺).

[0183] Similarly prepared were:

EXAMPLE 2 2-[4-(4-Chlorophenoxy)piperidine-1-sulfonyl]benzoic acid

[0184] From Intermediate 8 (830 mg) as a white foam (0.53 g, 66%).

[0185] R_(f) 0.58 (10% methanol/dichloromethane);

[0186] MS 396.5 (MH⁺).

EXAMPLE 3 2-[4-(4-Difluoromethoxyphenyl)piperazine-1-sulfonyl]benzoicacid

[0187] From Intermediate 9 (850 mg) as a beige solid (0.53 g, 80%).

[0188] R_(f) 0.35 (10% methanol/dichloromethane);

[0189] MS 412 (M⁺).

EXAMPLE 4 2-[4-(3,5-Dichlorophenyl)piperazine-1-sulfonyl]benzoic acid

[0190] From Intermediate 10 (760 mg) as a yellow solid (0.55 g, 75%).

[0191] R_(f) 0.52 (10% methanol/dichloromethane);

[0192] MS 415 (M⁺).

EXAMPLE 52-[4-(4-Trifluoromethylpyridin-2-yl)piperazine-1-sulfonyl]benzoic acid

[0193] From Intermediate 11 (830 mg) as a white foam (0.58 g, 93%).

[0194] R_(f) 0.58 (10% methanol/dichloromethane);

[0195] MS 416 (MH⁺).

EXAMPLE 6 2-[4-(4-Chlorobenzoyl)piperidine-1-sulfonyl]benzoic acid

[0196] From Intermediate 12 (266 mg) as a white foam (0.18 g, 70%).

[0197] R_(f) 0.46 (10% methanol/dichloromethane);

[0198] MS 408.5 (MH⁺).

EXAMPLE 7 2-(4-Benzylpiperidine-1-sulfonyl)benzoic acid

[0199] From Intermediate 13 (652 mg) as a cream solid (430 mg, 68%).

[0200] R_(f) 0.35 (10% methanol/dichloromethane);

[0201] MS 359 (M⁺).

EXAMPLE 8 2-[(4-Methoxyphenyl)methylsulfamoyl]benzoic acid

[0202] From Intermediate 14 (242 mg) as a beige solid (148 mg, 64%).

[0203] R_(f) 0.1 (5% methanol/dichloromethane);

[0204] MS 321 (M⁺).

EXAMPLE 9 2-[(4-(Pyridin-2-yl)piperazine-1-sulfonyl]benzoic acid

[0205] From Intermediate 15 (630 mg) as a white solid (200 mg, 35%).

[0206] R_(f) 0.20 (10% methanol/dichloromethane);

[0207] MS 347 (M⁺).

EXAMPLE 10 2-(3,4-Dihydro-1H-isoquinoline-2-sulfonyl)benzoic acid

[0208] From Intermediate 16 (475 mg) as a white solid (368 mg, 81%).

[0209] R_(f) 0.3 (5% methanol/dichloromethane);

[0210] MS 317 (M⁺).

EXAMPLE 11 N-Hydroxy-2-[4-(4-Chlorophenyl)piperazine-1-sulfonyl]benzamide

[0211] To a stirred solution of Example 1 (1.00 g) and oxalyl chloride(1.15 ml) in dichloromethane (30 ml) at RT was added DMF (1 drop).Stirring was continued at this temperature for 1 h before the solventwas removed under reduced pressure. The residue was azeotroped with 1:1hexane/dichloromethane (3×60 ml) and then dispersed in THF. Thesuspension was cooled to 0° C. and treated with a solution ofhydroxylamine (0.8 ml, 50% w/w). The reaction was stirred for 1 h at RTand then the solvent was removed under reduced pressure. The residue wastreated with water (30 ml) and stirred for 1.5 h. The solid wascollected and dried to give the title compound (1.00 g, 96%) as a whitesolid.

[0212] R_(f) 0.56 (ethyl acetate);

[0213] MS 410.7 (MH⁺).

[0214] Similarly prepared were:

EXAMPLE 12N-Hydroxy-2-[4-(4-Chlorophenoxy)piperidine-1-sulfonyl]benzamide

[0215] From Example 2 (0.54 g) as a beige foam (0.3 g, 54%).

[0216] R_(f) 0.48 (10% methanol/dichloromethane);

[0217] MS 411 (MH⁺).

EXAMPLE 13N-Hydroxy-2-[4-(4-Difluoromethoxyphenyl)piperazine-1-sulfonyl]benzamide

[0218] From Example 3 (0.65 g) as a beige foam (0.28 g, 41%).

[0219] R_(f) 0.42 (10% methanol/dichloromethane);

[0220] MS 427 (M⁺).

EXAMPLE 14N-Hydroxy-2-[4-(3,5-Dichlorophenyl)piperazine-1-sulfonyl]benzamide

[0221] From Example 4 (0.55 g) as a beige solid (0.29 g, 52%).

[0222] R_(f) 0.51 (10% methanol/dichloromethane);

[0223] MS 430 (M⁺).

EXAMPLE 15N-Hydroxy-2-[4-(4-Trifluoromethylpyridin-2-yl)piperazine-1-sulfonyl]benzamide

[0224] From Example 5 (0.75 g) as a pale yellow solid (0.29 g, 37%).

[0225] R_(f) 0.6 (10% methanol/dichloromethane);

[0226] MS 430 (M⁺).

EXAMPLE 16N-Hydroxy-2-[4-(4-Chlorobenzoyl)piperidine-1-sulfonyl]benzamide

[0227] From Example 6 (460 mg) as a white foam (0.12 g, 25%).

[0228] R_(f) 0.25 (5% methanol/dichloromethane);

[0229] MS 423.5 (MH⁺).

EXAMPLE 17 N-Hydroxy-2-(4-Benzylpiperidine-1-sulfonyl)benzamide

[0230] From Example 7 (400 mg) as a beige solid (56 mg, 13%).

[0231] R_(f) 0.45 (10% methanol/dichloromethane);

[0232] MS 375.5 (MH⁺).

EXAMPLE 18 N-Hydroxy-2-[(4-methoxyphenyl)methylsulfamoyl]benzamide

[0233] From Example 8 (145 mg) as a beige solid (33 mg, 20%).

[0234] R_(f) 0.25 (5% methanol/dichloromethane);

[0235] MS 337 (MH⁺).

EXAMPLE 19 N-Hydroxy-2-[4-(pyridin-2-yl)piperazine-1-sulfonyl]benzamide

[0236] From Example 9 (200 mg) as a white solid (43 mg, 21%).

[0237] R_(f) 0.42 (10% methanol/dichloromethane).

EXAMPLE 20 2-(3,4-Dihydro-1H-isoquinoline-2-sulfonyl)-N-hydroxybenzamide

[0238] From Example 10 (365 mg) as a white solid (59 mg, 15%).

[0239] R_(f) 0.44 (10% methanol/dichloromethane);

[0240] MS 332 (M⁺).

EXAMPLE 21 2-[4-(4-Chlorophenyl)piperazine-1-sulfonylmethyl]benzoic acid

[0241] To a stirred solution of Intermediate 19 (0.25 g) in 1:1:1methanol/THF/water (30 ml) was added lithium hydroxide monohydrate (0.5g). The resulting suspension was heated to reflux for 2.5 h. On coolingthe solvent was removed under reduced pressure and the resulting residuepartitioned between diethyl ether (50 ml) and water (20 ml). The aqueouslayer was collected and acidified to pH 5 with citric acid. The aqueousmixture was then extracted with ethyl acetate (3×50 ml) and the combinedorganic layers washed with water (10 ml) and brine (10 ml). Followingdrying (Na₂SO₄), the solvent was removed under reduced pressure to givea pale brown oil. The material was dissolved in a minimum volume ofethyl acetate and treated with excess hexane to give a precipitate.Filtration and washing with diethyl ether (3×5 ml) gave the titlecompound (113 mg, 46%) as a white solid.

[0242] R_(f) 0.62 (10% methanol/dichloromethane);

[0243] MS 395.5 (MH⁺).

[0244] Similarly prepared were:

EXAMPLE 22 2-[4-(4-Chlorophenoxy)piperidine-1-sulfonylmethyl]benzoicacid

[0245] From Intermediate 20 (300 mg) as a white solid (240 mg, 44%).

[0246] R_(f) 0.35 (10% methanol/dichloromethane).

EXAMPLE 23 2-[4-(4-Chlorobenzoyl)piperidine-1-sulfonylmethyl]benzoicacid

[0247] From Intermediate 21 (400 mg) as a white solid (350 mg, 90%).

[0248] R_(f) 0.30 (10% methanol/dichloromethane);

[0249] MS 422 (MH⁺).

EXAMPLE 24 2-(3,4-Dihydro-1H-isoquinoline-2-sulfonylmethyl)benzoic acid

[0250] From Intermediate 22 (400 mg) as a white solid (261 mg, 68%).

[0251] R_(f) 0.10 (5% methanol/dichloromethane);

[0252] MS 332 (MH⁺).

EXAMPLE 25 2-[(Benzofuran-2-ylmethyl-methyl-sulfamoyl)methyl]benzoicacid

[0253] From Intermediate 23 (232 mg) as a white solid (57 mg, 25%).

[0254] R_(f) 0.15 (5% methanol/dichloromethane);

[0255] MS 358 (MH⁻).

EXAMPLE 26 2-[4-(Pyridin-2-yl)piperazine-1-sulfonylmethyl]benzoic acid

[0256] From Intermediate 24 (686 mg) as a white solid (104 mg, 15%).

[0257] R_(f) 0.21 (5% methanol/dichloromethane);

[0258] MS 362 (MH⁺).

EXAMPLE 272-[4-(5-Trifluoromethylpyridin-2-yl)piperazine-1-sulfonylmethyl]benzoicacid

[0259] From Intermediate 25 (712 mg) as a white solid (110 mg, 16%).

[0260] R_(f) 0.26 (10% methanol/dichloromethane);

[0261] MS 430 (MH⁺).

EXAMPLE 282-[4-[4-(1,1-Difluoromethoxy)phenyl]piperazine-1-sulfonylmethyl]benzoicacid

[0262] From Intermediate 26 (367 mg) as a pink solid (176 mg, 49%).

[0263] R_(f) 0.30 (10% methanol/dichloromethane);

[0264] MS 427 (MH⁺).

EXAMPLE 29 2-([(4-Methoxyphenyl)methyl-sulfamoyl]methyl)benzoic acid

[0265] From Intermediate 27 (429 mg) as a white solid (309 mg, 75%).

[0266] R_(f) 0.30 (10% methanol/dichloromethane);

[0267] MS 334 (MH⁺).

EXAMPLE 302-[4-(4-Chlorophenyl)piperazine-1-sulfonylmethyl]-N-hydroxybenzamide

[0268] To a stirred solution of Example 21 (0.16 g) and oxalyl chloride(1 ml) in dichloromethane (10 ml) at RT was added DMF, with evolution ofgas. Stirring was continued at this temperature for 2 h before thesolvent was removed under reduced pressure. The residue was azeotropedwith 1:1 hexane/dichloromethane (3×20 ml) and then dispersed in THF. Thesuspension was cooled to 0° C. and treated with a 50% by weight solutionof hydroxylamine in water (1 ml). The reaction was stirred for 1 h at RTand then the solvent was removed under reduced pressure. The residue waspartitioned between ethyl acetate (50 ml) and water (20 ml). Collectionof the organic layer was followed by washing of this layer withsaturated aqueous sodium hydrogen carbonate solution (10 ml), water (5ml) and brine (10 ml). The resulting extracts were dried (Na₂SO₄) andthe solvent removed under reduced pressure to give a pale brown oil.This material was dissolved in a minimum volume of ethyl acetate andthen treated with excess hexane to give a precipitate. The solid wascollected by filtration, washing with diethyl ether (3×10 ml) to givethe title compound (0.02 g, 14%) as a beige solid.

[0269] R_(f) 0.62 (10% methanol/dichloromethane);

[0270] MS 410.7 (MH⁺).

[0271] Similarly prepared were:

EXAMPLE 312-[4-(4-Chlorophenoxy)piperidine-1-sulphonylmethyl]-N-hydroxybenzamide

[0272] From Example 22 (240 mg) as a white solid (25 mg, 10% ).

[0273] R_(f) 0.25 (5% methanol/dichloromethane);

[0274] MS 425.6 (MH⁺).

EXAMPLE 322-[4-(4-Chlorobenzoyl)piperidine-1-sulfonylmethyl]-N-hydroxybenzamide

[0275] From Example 23 (370 mg) as a beige solid (15 mg, 4%).

[0276] R_(f) 0.3 (5% methanol/dichloromethane);

[0277] MS 437.5 (MH⁺).

EXAMPLE 332-(3,4-Dihydro-1H-isoquinoline-2-sulfonylmethyl)-N-hydroxybenzamide

[0278] From Example 24 (261 mg) as a white solid (75 mg, 30%).

[0279] R_(f) 0.21 (5% methanol/dichloromethane);

[0280] MS 347 (M⁺).

EXAMPLE 342-[(Benzofuran-2-ylmethyl-methyl-sulfamoyl)methyl]-N-hydroxybenzamide

[0281] From Example 25 (50 mg) as a white solid (22 mg, 44%).

[0282] R_(f) 0.21 (5% methanol/dichloromethane),

[0283] MS 375 (MH⁺).

EXAMPLE 35N-Hydroxy-2-4-(5-trifluromethylpyridin-2-yl)piperazine-1-sulfonylmethyl]benzamide

[0284] From Example 27 (100 mg) as a white solid (42 mg, 40%).

[0285] R_(f) 0.16 (5% methanol/dichloromethane);

[0286] MS 443 (MH⁻).

EXAMPLE 362-{4-[4-(1,1-Difluoromethoxy)phenyl]piperazine-1-sulphonylmethyl}-N-hydroxybenzamide

[0287] From Example 28 (166 mg) as a white solid (93 mg, 54%).

[0288] R_(f) 0.23 (5% methanol/dichloromethane);

[0289] MS 440 (MH⁻).

EXAMPLE 37N-Hydroxy-2-{[(4-methoxyphenyl)methylsulfamoyl]methyl}benzamide

[0290] From Example 29 (289 mg) as a white solid (138 mg, 45%).

[0291] R_(f) 0.28 (10% methanol/dichloromethane);

[0292] MS 349 (MH⁻).

EXAMPLE 38 {2-[4-(4-Chlorophenyl)piperazine-1-sulfonyl]phenyl}aceticacid

[0293] A mixture of Intermediate 22 (417 mg) and 1M sodium hydroxidesolution (30 ml) was refluxed for 72 hours. The mixture was cooled andacidified to pH1 with 6M hydrochloric acid. The mixture was extractedwith ethyl acetate (4×20 ml) and the combined extracts were washed withwater (2×20 ml), brine (20 ml) and dried (MgSO₄). The mixture wasfiltered and evaporated to dryness to give the title compound as a paleyellow solid (360 mg, 82%).

[0294] R_(f) 0.23 (1:1 ethyl acetate/hexane);

[0295] MS 395 (MH⁺).

[0296] Similarly prepared were:

EXAMPLE 39 {2-[(4-Methoxyphenyl)methyl-sulfamoyl]phenyl}acetic acid

[0297] From Intermediate 23 (230 mg) as a white solid (242 mg, 99%).

[0298] R_(f) 0.35 (2:1 ethyl acetate/hexane);

[0299] MS 336 (MH⁺).

EXAMPLE 40{2-[4-(4-Difluoromethoxyphenyl)piperazine-1-sulfonyl]phenyl}acetic acid

[0300] From Intermediate 30 (530 mg) as a brown oil (145 mg, 26%).

[0301] R_(f) 0.10 (2:1 ethyl acetate/hexane);

[0302] MS 426 (MH⁺).

EXAMPLE 41{2-[4-(5-Trifluoromethylpyridin-2-yl)piperazine-1-sulfonyl]phenyl}aceticacid

[0303] From Intermediate 31 (660 mg) as an off white solid (609 mg,85%).

[0304] R_(f) 0.25 (10:1 dichloromethane/methanol);

[0305] MS 430 (MH⁺).

EXAMPLE 42{4,5-Dimethoxy-2-[4-(5-trifluoromethylpyridin-2-yl)piperazine-1-sulfonyl]phenyl}aceticacid

[0306]{4,5-Dimethoxy-2-[4-(5-trifluoromethylpyridin-2-yl)piperazine-1-sulfonyl]phenyl}aceticacid methyl ester (0.3 g) was taken up in methanol (10 ml),tetrahydrofuran (10 ml) and water (10 ml). Lithium hydroxide (125 mg)was added and the reaction stirred at RT for 16 hrs. The reaction wasdiluted with water (10 ml), its volume reduced to one was acidified topH 4 with 2M hydrochloric acid and extracted with ethyl acetate (4×25ml). The combined ethyl acetate extracts were washed with water (25 ml)and brine (25 ml) and dried over sodium sulphate. The solvent wasremoved in vacuo to yield the title compound as a white solid (291 mg,100%).

[0307] R_(f) 0.19 (2:1 ethyl acetate/hexane);

[0308] MS 490 (MH⁺).

EXAMPLE 432-{2-[4-(4-Chlorophenyl)piperazine-1-sulfonyl]phenyl}-3-methylbutyricacid

[0309] Intermediate 32 (0.23 g) was taken up in ethylene glycol (25 ml)with potassium hydroxide (155 mg) and heated at 150° C. for 72 hrs.After cooling the reaction was diluted with water (50 ml), and extractedwith diethyl ether (3×15 ml). The aqueous layer was acidified to pH 1with 2M hydrochloric acid, and extracted with ethyl acetate (4×25 ml).The combined ethyl acetate extracts were washed with water (2×25 ml),brine (25 ml) and dried over magnesium sulphate The solvent was removedin vacuo to yield a brown oil which was purified by flash chromatography(eluent 2:1 hexane/ethyl acetate) to yield the title compound as a whitesolid (152 mg, 63%).

[0310] R_(f) 0.18 (1:2 ethyl acetate/hexane);

[0311] MS 437 (MH⁺).

EXAMPLE 44 [2-(Benzofuran-2-ylmethyl-methyl-sulfamoyl)phenyl]acetic acid

[0312] To stirred suspension of Intermediate 6 (322 mg) indichloromethane (20 ml) at RT was added triethylamine (0.84 ml). After15 min, a solution of Intermediate 5 (431 mg) in dichloromethane (5 ml)was added. Stirring was continued for 1 h before the solvent was removedin vacuo. The residue was treated with sodium hydroxide solution (3M, 20ml) and refluxed for 24 h. The mixture was cooled, washed with diethylether (20 ml) and acidified to pH3 with 2M hydrochloric acid andextracted with ethyl acetate (4×20 ml). The combined ethyl acetatelayers were washed with water (20 ml), brine (20 ml) and dried overmagnesium sulphate. Filtration and evaporation of the solvent yieldedthe title compound as an off-white solid (159 mg, 22%).

[0313] R_(f) 0.30 (2:1 ethyl acetate/hexane);

[0314] MS 360 (MH⁺).

[0315] Similarly prepared were:

EXAMPLE 45 [2-[4-(Pyridin-2-yl)piperazine-1-sulfonyl]phenyl]acetic acid

[0316] From Intermediate 5 (431 mg) and 4-(2-pyridinyl)piperazine (326mg) as an off-white solid (335 mg, 46%).

[0317] R_(f) 0.05 (2:1 ethyl acetate/hexane);

[0318] MS 362 (MH⁺).

EXAMPLE 46 {2-[4-(3,5-Dichlorophenyl)piperazine-1-sulfonyl]phenyl}aceticacid

[0319] From Intermediate 5 (431 mg) and 4-(3,5-dichlorophenyl)piperazine(462 mg) as an off-white solid (265 mg, 31%).

[0320] R_(f) 0.43 (2:1 ethyl acetate/hexane);

[0321] MS 430 (MH⁺).

EXAMPLE 47 {2-[4-(4-Chlorophenoxy)piperidine-1-sulfonyl]phenyl}aceticacid

[0322] From Intermediate 5 (431 mg) and 4-(4-chlorophenoxy)piperidine(496 mg) as an off-white solid (206 mg, 25%).

[0323] R_(f) 0.33 (2:1 ethyl acetate/hexane);

[0324] MS 410 (MH⁺).

EXAMPLE 48 [2-(4-Chlorobenzoylpiperidine-1-sulfonyl)phenyl]acetic acid

[0325] From Intermediate 5 (431 mg) and 4-(4-chlorobenzoyl)piperidine(520 mg) as an off-white solid (377 mg, 45%).

[0326] R_(f) 0.26 (2:1 ethyl acetate/hexane);

[0327] MS 422 (MH⁺).

EXAMPLE 49 [2-(3,4-Dihydro-1H-isoquinoline-2-sulfonyl)phenyl]acetic acid

[0328] From Intermediate 5 (431 mg) and 3,4-dihydro-1H-isoquinoline (266mg) as an off-white solid (416 mg, 63%).

[0329] R_(f) 0.38 (2:1 ethyl acetate/hexane);

[0330] MS 332 (MH⁺).

EXAMPLE 50{2-[4-(4-Chlorophenyl)piperazine-1-sulfonyl]phenyl}-N-hydroxyacetamide

[0331] To a stirred solution of Example 38 (0.35 g) and oxalyl chloride(2 ml) in dichloromethane (20 ml) at RT was added DMF, with evolution ofgas. Stirring was continued at this temperature for 2 h before thesolvent was removed under reduced pressure. The residue was azeotropedwith 1:1 hexane/dichloromethane (3×20 ml) and then dispersed in THF. Thesuspension was cooled to 0° C. and treated with a 50% by weight solutionof hydroxylamine in water (1 ml). The reaction was stirred for 1 hour atRT and then the solvent was removed under reduced pressure. The residuepartitioned between ethyl acetate (50 ml) and water (20 ml). Collectionof the organic layer was followed by washing of this layer withsaturated aqueous sodium hydrogen carbonate solution (10 ml), water (5ml) and brine (10 ml). The resulting extracts were dried over sodiumsulphate and the solvent removed under reduced pressure to give a palebrown oil. This material was dissolved in a minimum volume of ethylacetate and then treated with excess hexane to give a precipitate. Thesolid was collected by filtration, washing with diethyl ether (3×10 ml)to give the title compound (238 mg, 66%) as an off-white solid.

[0332] R_(f) 0.42 (5:1 ethyl acetate/hexane);

[0333] MS 410 (MH⁺).

[0334] Similarly prepared were:

EXAMPLE 51{2-[(4-Methoxyphenyl)methyl-sulfamoyl]phenyl}-N-hydroxyacetamide

[0335] From Example 39 (229 mg) as an off-white solid (218 mg, 91%).

[0336] R_(f) 0.36 (10:1 dichloromethane/methanol);

[0337] MS 351 (MH⁺).

EXAMPLE 522-{2-[4-(4-Difluoromethoxyphenyl)piperazine-1-sulfonyl]phenyl}-N-hydroxyacetamide

[0338] From Example 40 (135 mg) as a brown solid (86 mg, 61%).

[0339] R_(f) 0.38 (10:1 dichloromethane/methanol);

[0340] MS 441 (MH⁺).

EXAMPLE 53N-Hydroxy-2-{2-[4-(5-trifluoromethylpyridin-2-yl)piperazine-1-sulfonyl]phenyl}acetamide

[0341] From Example 41 (135 mg) as an off-white solid (503 mg, 82%).

[0342] R_(f) 0.42 (10:1 dichloromethane/methanol);

[0343] MS 444 (MH⁺).

EXAMPLE 542-{4,5-Dimethoxy-2-[4-(5-trifluoromethylpyridin-2-yl)piperazine-1-sulfonyl]phenyl}-N-hydroxyacetamide

[0344] From Example 42 (260 mg) as a white solid (237 mg, 88%).

[0345] R_(f) 0.29 (10:1 dichloromethane/methanol);

[0346] MS 504 (MH⁺).

EXAMPLE 55 2-{2-[4-(4-Chlorophenyl)piperazine-1-sulfonyl]phenyl}-N-hydroxy-3-methylbutyramide

[0347] From Example 43 (115 mg) as a white solid (113 mg, 95%).

[0348] R_(f) 0.37 (10:1 dichloromethane/methanol);

[0349] MS 451 (MH⁺).

EXAMPLE 56[2-(Benzofuran-2-ylmethyl-methyl-sulfamoyl)phenyl]-N-hydroxyacetamide

[0350] From Example 44 (155 mg) as an off-white solid (106 mg, 66%).

[0351] R_(f) 0.37 (10:1 dichloromethane/methanol);

[0352] MS 375 (MH⁺).

EXAMPLE 57[2-[(4-Pyridin-2-yl)piperazine-1-sulfonyl]phenyl]-N-hydroxyacetamide

[0353] From Example 45 (330 mg) as an off-white solid (306 mg, 86%).

[0354] R_(f) 0.27 (10:1 dichloromethane/methanol);

[0355] MS 389 (MH⁺).

EXAMPLE 582-{2-[4-(3,5-Dichlorophenyl)piperazine-1-sulfonyl]phenyl}-N-hydroxyacetamide

[0356] From Example 46 (260 mg) as an off-white solid (230 mg, 86%).

[0357] R_(f) 0.36 (10:1 dichloromethane/methanol);

[0358] MS 445 (MH⁺).

EXAMPLE 59{2-[4-(4-Chlorophenoxy)piperidine-1-sulfonyl]phenyl}-N-hydroxyacetamide

[0359] From Example 47 (201 mg) as an off-white solid (94 mg, 45%).

[0360] R_(f) 0.37 (10:1 dichloromethane/methanol);

[0361] MS 424 (MH⁺).

EXAMPLE 60[2-(4-Chlorobenzoylpiperidine-1-sulfonyl)phenyl]-N-hydroxyacetamide

[0362] From Example 48 (372 mg) as an off-white solid (290 mg, 75%).

[0363] R_(f) 0.36 (10:1 dichloromethane/methanol);

[0364] MS 437 (MH⁺).

EXAMPLE 612-(2-{4-[(4-Chlorophenyl)hydroxyiminomethyl]piperidine-1-sulfonyl}phenyl)-N-hydroxyacetamide

[0365] From Example 48 (372 mg) as an off-white solid (32 mg, 8%).

[0366] R_(f) 0.40 (10:1 dichloromethane/methanol);

[0367] MS 451 (MH⁺).

EXAMPLE 62[2-(3,4-Dihydro-1H-isoquinoline-2-sulfonyl)phenyl]-N-hydroxyacetamide

[0368] From Example 49 (300 mg) as an off-white solid (212 mg, 74%).

[0369] R_(f) 0.37 (10:1 dichloromethane/methanol);

[0370] MS 346 (MH⁺).

EXAMPLE 63 3-[4-(4-Chlorophenyl)piperazine-1-sulfonyl]benzoic acid

[0371] To a suspension of 1-(4-chlorophenyl)piperazine dihydrochloride(539 mg) and 3-(chlorosulfonyl)benzoic acid (441 mg) in dichloromethane(50 ml) was added diisopropylethylamine (0.8 ml). After stirringovernight at room temperature the reaction mixture was washed with 2NHCl (3×25 ml) and brine (25 ml), dried over MgSO₄, filtered andevaporated to give the title compound as white solid (290 mg, 38%).

[0372] MS 381 (M⁺).

EXAMPLE 643-[4-(4-Chlorophenyl)piperazine-1-sulfonyl]-N-hydroxybenzamide

[0373] To a suspension of Example 63 (190 mg) was addedO-(tert-butyldimetliylsilyl)hydroxylamine (81 mg) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (96 mg).After stirring overnight at room temperature ethyl acetate (100 mL) wasadded and the organic layer was washed with water (2×25 ml), saturatedNaHCO₃ (2×25 ml) and water (25 ml), dried over MgSO₄, filtered andevaporated. The colourless oil was dissolved in dichloromethane (20 ml)and treated with 1.0 M HCl solution in ether (1.5 ml). Filtrationafforded the title compound as a white solid (100 mg, 50%).

[0374] R_(f) 0.6 (10% methanol in dichloromethane);

[0375] MS 396 (M⁺).

1. A compound of formula (I) (B)₂N—X—(CH₂)_(m)-W-(CR¹R²)_(n)—COY  (I)wherein n=0 or 1; m=0 or 1; X is S(O)₁₋₂; Y is OH or NHOH; W is aryl orheteroaryl; R¹ is H, OR⁷ or a group (optionally substituted with R³)selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, C₁₋₆alkyl-aryl, heteroaryl, C₁₋₆ alkyl-heteroaryl, cycloalkyl, C₁₋₆alkyl-cycloalkyl, heterocycloalkyl or C₁₋₆ alkyl-heterocycloalkyl; andR² is H or C₁₋₆ alkyl; or CR¹R² is cycloalkyl or heterocycloalkyloptionally substituted with R³ or a group (optionally substituted withR³) selected from C₁₋₆ alkyl, aryl, C₁₋₆ alkyl-aryl, heteroaryl or C₁₋₆alkyl-heteroaryl; R³ is OR⁷, COR⁷, CO₂R⁸, CON(R⁷)₂, N(R⁷)₂, NR⁷COR⁷,NR⁷CON(R⁷)₂, NR⁷CO₂R⁸, NR⁷SO₂R⁸, S(O)₀₋₂R⁸, SO₂N(R⁷)₂ or cycloimidyl(optionally substituted with R⁴); R⁴ is C₁₋₆ alkyl; B is H or a group(optionally substituted with R⁵ or R⁶) selected from C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, C₁₋₆ alkyl-aryl, heteroaryl, C₁₋₆alkyl-heteroaryl, cycloalkyl, C₁₋₆ alkyl-cycloalkyl, heterocycloalkyl,C₁₋₆ alkyl-heterocycloalkyl, cycloalkenyl, or heterocycloalkenyl; andeach instance of B may be the same or different; or B-N-B isheterocycloalkyl optionally substituted with R⁵, R⁶, ═O or ═NOR⁵; R⁵ isa group (optionally substituted with R⁶) selected from C₁₋₆ alkyl, aryl,C₁₋₆ alkyl-aryl, heteroaryl, C₁₋₆ alkyl-heteroaryl, cycloalkyl, C₁₋₆alkyl-cycloalkyl, heterocycloalkyl or C₁₋₆ alkyl-heterocycloalkyl; R⁶ isa group selected from N(R⁷)₂, NR⁷COR⁷, NR⁷CON(R⁷)₂, NR⁷CO₂R⁸, NR⁷SO₂R⁸,OR⁷, COR⁷, CO₂R⁴, CON(R⁷)₂, S(O)₀₋₂R⁸ or SO₂N(R⁷)₂; R⁷ is H or a groupselected from C₁₋₆ alkyl, aryl, C₁₋₆ alkyl-aryl, heteroaryl, C₁₋₆alkyl-heteroaryl, cycloalkyl, C₁₋₆ alkyl-cycloalkyl, heterocycloalkyl orC₁₋₆ alkyl-heterocycloalkyl, wherein said group is optionallysubstituted with R⁸, COR⁸, SO₀₋₂R⁸, CO₂R⁸, OR⁸, CONR⁴R⁸, NR⁴R⁸ orSO₂NR⁴R⁸ and for each case of N(R⁷)₂ the R⁷ groups are the same ordifferent or N(R⁷)₂ is heterocycloalkyl optionally substituted with R⁸,COR⁸, S(O)₀₋₂R⁸, CO₂R⁸, OR⁸, CONR⁴R⁸, NR⁴R⁸ or SO₂ NR⁴R⁸; and R⁸ is C₁₋₆alkyl, aryl, C₁₋₆ alkyl-aryl, heteroaryl or C₁₋₆ alkyl-heteroaryl; or asalt, solvate, hydrate, N-oxide, protected amino, protected carboxy orprotected hydroxamic acid derivative thereof.
 2. The compound accordingto claim 1, wherein X is SO₂.
 3. The compound according to claim 1,wherein B-N-B is optionally substituted heterocycloalkyl.
 4. Thecompound according to claim 2, wherein B-N-B is optionally substitutedheterocycloalkyl.
 5. The compound according to claim 1, wherein Y is OH,m and n are both zero, and B-N-B is optionally substitutedheterocycloalkyl.
 6. The compound according to claim 1, wherein Y is OH,with the proviso that m and n are not both zero.
 7. The compoundaccording to claim 1, wherein Y is NHOH.
 8. The compound according toclaim 6, wherein m=1.
 9. The compound according to claim 7, wherein m=1.10. The compound according to claim 6, wherein n=1.
 11. The compoundaccording to claim 7, wherein n=1.
 12. The compound according to claim8, wherein n=1.
 13. The compound according to claim 6, wherein m=1 andn=1.
 14. The compound according to claim 7, wherein m=1 and n=1.
 15. Thecompound according to claim 6, wherein at least one B is substitutedC₁₋₆ alkyl-aryl.
 16. The compound according to claim 1, wherein B is Hor a group (optionally substituted with R⁵ or R⁶) selected from C₁₋₆alkyl, C₂ ₆ alkenyl, C₂₋₆ alkynyl, heteroaryl, C₁₋₆ alkyl-heteroaryl,cycloalkyl, C₁₋₆ alkyl-cycloalkyl, heterocycloalkyl, C₁₋₆alkyl-heterocycloalkyl, cycloalkenyl or heterocycloalkenyl; and eachinstance of B may be the same or different.
 17. The compound accordingto claim 16, wherein B is H or a group (optionally substituted with R⁵or R⁶) selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,heterocycloalkyl, C₁₋₆ alkylcycloalkyl, heterocycloalkyl, C₁₋₆alkyl-heterocycloalkyl, cycloalkenyl or heterocycloalkenyl; and eachinstance of B may be the same or different.
 18. The compound accordingto claim 1, wherein neither B is H.
 19. The compound according to claim18, wherein B-N-B is heterocycloalkyl substituted with a substitutedC₁₋₆ alkyl-aryl group.
 20. The compound according to claim 18, whereinB-N-B is heterocycloalkyl substituted with NOR⁵, R⁶ or a group(optionally substituted with R⁶) selected from C₁₋₆ alkyl, aryl,heteroaryl, C₁₋₆ alkyl-heteroaryl, cycloalkyl, C₁₋₆ alkyl-cycloalkyl,heterocycloalkyl or C₁₋₆ alkyl-heterocycloalkyl.
 21. The compoundaccording to claim 18, wherein B-N-B is heterocycloalkyl substitutedwith NOR⁵, R⁶ or a group (optionally substituted with R⁶) selected fromC₁₋₆ alkyl, aryl, heteroaryl, cycloalkyl, C₁₋₆ alkyl-cycloalkyl,heterocycloalkyl or C₁₋₆ alkyl-heterocycloalkyl.
 22. The compoundaccording to claim 18, wherein B-N-B is heterocycloalkyl substitutedwith NOR⁵, R⁶ or a group (optionally substituted with R⁶) selected fromC₁₋₆ alkyl, cycloalkyl, C₁₋₆ alkyl-cycloalkyl, heterocycloalkyl or C₁₋₆alkyl-heterocycloalkyl.
 23. The compound according to claim 1, selectedfrom the group consisting of2-[4-(4-chlorophenyl)piperazine-1-sulfonyl]benzoic acid,2-[4-(4-chlorophenoxy)piperidine-1-sulfonyl]benzoic acid,2-[4-(4-difluoromethoxyphenyl)piperazine-1-sulfonyl]benzoic acid,2-[4-(3,5-dichlorophenyl)piperazine-1-sulfonyl]benzoic acid,2-[4-(4-trifluoromethylpyridin-2-yl)piperazine-1-sulfonyl]benzoic acid,2-[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]benzoic acid,2-(4-benzylpiperidine-1-sulfonyl)benzoic acid,2-[4-(4-chlorophenyl)piperazine-1-sulfonylmethyl]benzoic acid,{2-[4-(4-chlorophenyl)piperazine-1-sulfonyl]phenyl}acetic acid,{2-[(4-methoxyphenyl)methyl-sulfamoyl]phenyl}acetic acid,[2-(benzofuran-2-yl-methyl-methyl-sulfamoyl)phenyl]acetic acid,[2-(4-pyridin-2-yl-piperazine-1-sulfonyl)phenyl]acetic acid,{2-[4-(3,5-dichlorophenyl)piperazine-1-sulfonyl]phenyl}acetic acid,{2-[4-(4-chlorophenoxy)piperidine-1-sulfonyl]phenyl}acetic acid,[2-(4-chlorobenzoylpiperidine-1-sulfonyl)phenyl]acetic acid, and[2-(3,4-dihydro-1H-isoquinoline-2-sulfonyl)phenyl]acetic acid.
 24. Thecompound according to claim 1, selected from the group consisting of2-[(4-methoxyphenyl)methylsulfamoyl]benzoic acid,2-[(4-(pyridin-2-yl)piperazine-1-sulfonyl]benzoic acid,2-(3,4-dihydro-1H-isoquinoline-2-sulfonyl)benzoic acid,2-[4-(4-chlorophenoxy)piperidine-1-sulfonylmethyl]benzoic acid,2-[4-(4-chlorobenzoyl)piperidine-1-sulfonylmethyl]benzoic acid,2-(3,4-dihydro-1H-isoquinoline-2-sulfonylmethyl)benzoic acid,2-[(benzofuran-2-ylmethyl-methyl-sulfamoyl)methyl]benzoic acid,2-[4-(pyridin-2-yl)piperazine-1-sulfonylmethyl]benzoic acid,2-[4-(5-trifluoromethylpyridin-2-yl)piperazine-1-sulfonylmethyl]benzoicacid,2-[4-[4-(1,1-difluoromethoxy)phenyl]piperazine-1-sulfonylmethyl]benzoicacid, 2-([(4-methoxyphenyl)methyl-sulfamoyl]methyl)benzoic acid,{2-[4-(5-trifluoromethylpyridin-2-yl)piperazine-1-sulfonyl]phenyl}aceticacid,{4,5-dimethoxy-2-[4-(5-trifluoromethylpyridin-2-yl)piperazine-1-sulfonyl]phenyl}aceticacid, and2-{2-[4-(4-chlorophenyl)piperazine-1-sulfonyl]phenyl}-3-methylbutyricacid.
 25. A pharmaceutical composition for use in therapy, comprising acompound of claim 1, and a pharmaceutically-acceptable diluent orcarrier.
 26. A method for the treatment or prevention of a conditionassociated with matrix metalloproteinase, ADAM or ADAM-TS enzymes, acondition that is mediated by TNF or a condition involving amembrane-shedding event that is mediated by a metalloproteinase, whereinsaid method comprises administering to a human or animal an effectiveamount of the compound of formula (I)(B)₂N—X—(CH₂)_(m)-W-(CR¹R²)_(n)—COY  (I) wherein n=0 or 1; m=0 or 1; Xis S(O)₁₋₂; Y is OH or NHOH; W is aryl or heteroaryl; R¹ is H, OR⁷ or agroup (optionally substituted with R³) selected from C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, C₁₋₆ alkyl-aryl, heteroaryl, C₁₋₆alkyl-heteroaryl, cycloalkyl, C₁₋₆ alkyl-cycloalkyl, heterocycloalkyl orC₁₋₆ alkyl-heterocycloalkyl; and R² is H or C₁₋₆ alkyl; or CR¹R² iscycloalkyl or heterocycloalkyl optionally substituted with R³ or a group(optionally substituted with R³) selected from C₁₋₆ alkyl, aryl, C₁₋₆alkyl-aryl, heteroaryl or C₁₋₆ alkyl-heteroaryl; R³ is OR⁷, COR⁷, CO₂R⁸,CON(R⁷)₂, N(R⁷)₂, NR⁷COR⁷, NR⁷CON(R⁷)₂, NR⁷CO₂R⁸, NR⁷SO₂R⁸, S(O)₀₋₂R⁸,SO₂N(R⁷)₂ or cycloimidyl (optionally substituted with R⁴); R⁴ is C₁₋₆alkyl; B is H or a group (optionally substituted with R⁵ or R⁶) selectedfrom C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, C₁₋₆ alkyl-aryl,heteroaryl, C₁₋₆ alkyl-heteroaryl, cycloalkyl, C₁₋₆ alkyl-cycloalkyl,heterocycloalkyl, C₁₋₆ alkyl-heterocycloalkyl, cycloalkenyl, orheterocycloalkenyl; and each instance of B may be the same or different;or B-N-B is heterocycloalkyl optionally substituted with R⁵, R⁶, ═O or═NOR⁵; R⁵ is a group (optionally substituted with R⁶) selected from C₁₋₆alkyl, aryl, C₁₋₆ alkyl-aryl, heteroaryl, C₁₋₆ alkyl-heteroaryl,cycloalkyl, C₁₋₆ alkyl-cycloalkyl, heterocycloalkyl or C₁₋₆alkyl-heterocycloalkyl; R⁶ is a group selected from N(R⁷)₂, NR⁷COR⁷,NR⁷CON(R⁷)₂, NR⁷CO₂R⁸, NR⁷SO₂R⁸, OR⁷, COR⁷, CO₂R⁴, CON(R⁷)₂, S(O)₀₋₂R⁸or SO₂N(R⁷)₂; R⁷ is H or a group selected from C₁₋₆ alkyl, aryl, C₁₋₆alkyl-aryl, heteroaryl, C₁₋₆ alkyl-heteroaryl, cycloalkyl, C₁₋₆alkyl-cycloalkyl, heterocycloalkyl or C₁₋₆ alkyl-heterocycloalkyl,wherein said group is optionally substituted with R⁸, COR⁸, SO₀₋₂R⁸,CO₂R⁸, OR⁸, CONR⁴R⁸, NR⁴R⁸ or S0 ₂NR⁴R⁸ and for each case of N(R⁷)₂ theR⁷ groups are the same or different or N(R⁷)₂ is heterocycloalkyloptionally substituted with R⁸, COR⁸, S(O)₀₋₂R⁸, CO₂R⁸, OR⁸, CONR⁴R⁸,NR⁴R⁸ or SO₂NR⁴R⁸; and R⁸ is C₁₋₆ alkyl, aryl, C₁₋₆ alkyl-aryl,heteroaryl or C₁₋₆ alkyl-heteroaryl; or a salt, solvate, hydrate,N-oxide, protected amino, protected carboxy or protected hydroxamic acidderivative thereof.
 27. The method according to claim 26, wherein X isSO₂.
 28. The method according to claim 26, wherein B-N-B is optionallysubstituted heterocycloalkyl.
 29. The method according to claim 27,wherein B-N-B is optionally substituted heterocycloalkyl.
 30. The methodaccording to claim 26, wherein the condition is selected from the groupconsisting of cancer, inflammation and inflammatory diseases, tissuedegeneration, periodontal disease, ophthalmological disease,dermatological disorders, fever, cardiovascular effects, haemorrhage,coagulation and acute phase response, cachexia, anorexia, acuteinfection, HIV infection, shock states, graft versus host reactions,autoimmune disease, reperfusion injury, meningitis, migraine andaspirin-independent anti-thrombosis.
 31. The method according to claim26, wherein the condition is selected from the group consisting oftumour growth, angiogenesis, tumour invasion and spread, metastasis,malignant ascites and malignant pleural effusion.
 32. The methodaccording to claim 26, wherein the condition is selected from the groupconsisting of cerebral ischaemia, ischaemic heart disease, rheumatoidarthritis, osteoarthritis, osteoporosis, asthma, multiple sclerosis,neurodegeneration, Alzheimer's, atherosclerosis, stroke and vasculitis.33. The method according to claim 26, wherein the condition is selectedfrom the group consisting of Crohn's disease, ulcerative colitis,corneal ulceration, retinopathy, surgical wound healing, psoriasis,atopic dermatitis, chronic ulcers, epidermolysis bullosa, periodontitis,gingivitis, rhinitis, allergic conjunctivitis, eczema, anaphylaxis,restenosis, congestive heart failure, endometriosis, atherosclerosis,endosclerosis, pelvic inflammatory disease (PID), cancer-induced boneresorption, age-related macular degeneration, lung disease, cysticfibrosis adult respiratory distress syndrome (ARDS), emphysema,bronchitis obliterans-organising pneumonia (BOOP), idiopathic pulmonaryfibrosis (PIF), diffuse alveolar damage, pulmonary Langerhan's cellgranulamatosis, pulmonary lymphangioleiomyomatosis (LAM) and chronicobstructive pulmonary disease (COPD).
 34. The method according to claim26, wherein the compound of formula (I) is selected from the groupconsisting of 2-[4-(4-chlorophenyl)piperazine-1-sulfonyl]benzoic acid,2-[4-(4-chlorophenoxy)piperidine-1-sulfonyl]benzoic acid,2-[4-(4-difluoromethoxyphenyl)piperazine-1-sulfonyl]benzoic acid,2-[4-(3,5-dichlorophenyl)piperazine-1-sulfonyl]benzoic acid,2-[4-(4-trifluoromethylpyridin-2-yl)piperazine-1-sulfonyl]benzoic acid,2-[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]benzoic acid,2-(4-benzylpiperidine-1-sulfonyl)benzoic acid,N-hydroxy-2-[4-(4-chlorophenyl)piperazine-1-sulfonyl]benzamide,N-hydroxy-2-[4-(4-chlorophenoxy)piperidine-1-sulfonyl]benzamide,N-hydroxy-2-[4-(4-difluoromethoxyphenyl)piperazine-1-sulfonyl]benzamide,N-hydroxy-2-[4-(3,5-dichlorophenyl)piperazine-1-sulfonyl]benzamide,N-hydroxy-2-[4-(4-trifluoromethylpyridin-2-yl)piperazine-1-sulfonyl]benzamide,N-hydroxy-2-[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]benzamide,N-hydroxy-2-(4-benzylpiperidine-1-sulfonyl)benzamide,2-[4-(4-chlorophenyl)piperazine-1-sulfonylmethyl]benzoic acid,{2-[4-(4-chlorophenyl)piperazine-1-sulfonyl]phenyl}acetic acid,{2-[(4-methoxyphenyl)methyl-sulfamoyl]phenyl}acetic acid,[2-(benzofuran-2-yl-methyl-methyl-sulfamoyl)phenyl]acetic acid,[2-(4-pyridin-2-yl-piperazine-1-sulfonyl)phenyl]acetic acid,{2-[4-(3,5-dichlorophenyl)piperazine-1-sulfonyl]phenyl}acetic acid,{2-[4-(4-chlorophenoxy)piperidine-1-sulfonyl]phenyl}acetic acid,[2-(4-chlorobenzoylpiperidine-1-sulfonyl)phenyl]acetic acid,[2-(3,4-dihydro-1H-isoquinoline-2-sulfonyl)phenyl]acetic acid,2-[4-(4-chlorophenyl)piperazine-1-sulfonylmethyl]-N-hydroxybenzamide,{2-[4-(4-chlorophenyl)piperazine-1-sulfonyl]phenyl}-N-hydroxyacetamide,[2-(benzofuran-2-yl-methyl-methyl-sulfamoyl)phenyl]-N-hydroxyacetamide,[2-(4-pyridin-2-yl-piperazine-1-sulfonyl)phenyl]-N-hydroxyacetamide,2-{2-[4-(3,5-dichlorophenyl)piperazine-1-sulfonyl]phenyl}-N-hydroxyacetamide,{2-[4-(4-chlorophenoxy)piperidine-1-sulfonyl]phenyl}-N-hydroxyacetamide,[2-(4-benzoylpiperidine-1-sulfonyl)phenyl]-N-hydroxyacetamide,[2-(3,4-dihydro-1H-isoquinoline-2-sulfonyl)phenyl]-N-hydroxyacetamide,and {2-[(4-methoxyphenyl)methyl-sulfamoyl]phenyl}-N-hydroxyacetamide.35. The method according to claim 26, wherein the compound of formula(I) is selected from the group consisting of:2-[(4-methoxyphenyl)methylsulfamoyl]benzoic acid,2-[(4-(pyridin-2-yl)piperazine-1-sulfonyl]benzoic acid,2-(3,4-dihydro-1H-isoquinoline-2-sulfonyl)benzoic acid,N-hydroxy-2-[(4-methoxyphenyl)methylsulfamoyl]benzamide,N-hydroxy-2-[4-(pyridin-2-yl)piperazine-1-sulfonyl]benzamide,2-(3,4-dihydro-1H-isoquinoline-2-sulfonyl)-N-hydroxybenzamide,2-[4-(4-chlorophenoxy)piperidine-1-sulfonylmethyl]benzoic acid,2-[4-(4-chlorobenzoyl)piperidine-1-sulfonylmethyl]benzoic acid,2-(3,4-dihydro-1H-isoquinoline-2-sulfonylmethyl)benzoic acid,2-[(benzofuran-2-ylmethyl-methyl-sulfamoyl)methyl]benzoic acid,2-[4-(pyridin-2-yl)piperazine-1-sulfonylmethyl]benzoic acid,2-[4-(5-trifluoromethylpyridin-2-yl)piperazine-1-sulfonylmethyl]benzoicacid,2-[4-[4-(1,1-difluoromethoxy)phenyl]piperazine-1-sulfonylmethyl]benzoicacid, 2-([(4-methoxyphenyl)methyl-sulfamoyl]methyl)benzoic acid,2-[4-(4-chlorophenoxy)piperidine-1-sulphonylmethyl]-N-hydroxybenzamide,2-[4-(4-chlorobenzoyl)piperidine-1-sulfonylmethyl]-N-hydroxybenzamide,2-(3,4-dihydro-1H-isoquinoline-2-sulfonylmethyl)-N-hydroxybenzamide,2-[(benzofuran-2-ylmethyl-methyl-sulfamoyl)methyl]-N-hydroxybenzamide,N-Hydroxy-2-[4-(5-trifluromethylpyridin-2-yl)piperazine-1-sulfonylmethyl]benzamide,2-{4-[4-(1,1-difluoromethoxy)phenyl]piperazine-1-sulphonylmethyl}-N-hydroxybenzamide,N-hydroxy-2-{[(4-methoxyphenyl)methyl-sulfamoyl]methyl}benzamide,{2-[4-(5-trifluoromethylpyridin-2-yl)piperazine-1-sulfonyl]phenyl}aceticacid,{4,5-dimethoxy-2-[4-(5-trifluoromethylpyridin-2-yl)piperazine-1-sulfonyl]phenyl}aceticacid,2-{2-[4-(4-chlorophenyl)piperazine-1-sulfonyl]phenyl}-3-methylbutyricacid,2-{2-[4-(4-difluoromethoxyphenyl)piperazine-1-sulfonyl]phenyl}-N-hydroxyacetamide,N-hydroxy-2-{2-[4-(5-trifluoromethylpyridin-2-yl)piperazine-1-sulfonyl]phenyl}acetamide,2-{4,5-dimethoxy-2-[4-(5-trifluoromethylpyridin-2-yl)-piperazine-1-sulfonyl]phenyl}-N-hydroxyacetamide,2-{2-[4-(4-chlorophenyl)piperazine-1-sulfonyl]phenyl}-N-hydroxy-3-methylbutyramide,2-(2-{4-[(4-chlorophenyl)hydroxyiminomethyl]piperidine-1-sulfonyl}phenyl)-N-hydroxyacetamide,3-[4-(4-chlorophenyl)piperazine-1-sulfonyl]benzoic acid, and3-[4-(4-chlorophenyl)piperazine-1-sulfonyl]-N-hydroxybenzamide.
 36. Amethod for the treatment or prevention of a condition associated withmatrix metalloproteinase, ADAM or ADAM-TS enzymes, a condition that ismediated by TNF or a condition involving a membrane-shedding event thatis mediated by a metalloproteinase, wherein said method comprisesadministering to a human or animal an effective amount of a compoundselected from the group consisting of: (a) a compound of formula (I)(B)₂N—X—(CH₂)_(m)-W-(CR¹R²)_(n)—COY  (I) wherein n=0; m=0; X is S(O)₁₋₂;Y is OH; W is aryl or heteroaryl; R¹ is H, OR⁷ or a group (optionallysubstituted with R³) selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, aryl, C₁₋₆ alkyl-aryl, heteroaryl, C₁₋₆ alkyl-heteroaryl,cycloalkyl, C₁₋₆ alkyl-cycloalkyl, heterocycloalkyl or C₁₋₆alkyl-heterocycloalkyl; and R² is H or C₁₋₆ alkyl; or CR¹R² iscycloalkyl or heterocycloalkyl optionally substituted with R³ or a group(optionally substituted with R³) selected from C₁₋₆ alkyl, aryl, C₁₋₆alkyl-aryl, heteroaryl or C₁₋₆ alkyl-heteroaryl; R³ is OR⁷, COR⁷, CO₂R⁸,CON(R⁷)₂, N(R⁷)₂, NR⁷COR⁷, NR⁷CON(R⁷)₂, NR⁷CO₂R⁸, NR⁷SO₂R⁸, S(O)₀₋₂R⁸,SO₂N(R⁷)₂ or cycloimidyl (optionally substituted with R⁴); R⁴ is C₁₋₆alkyl; B-N-B is heterocycloalkyl optionally substituted with R⁵, R⁶, ═Oor ═NOR⁵; R⁵ is a group (optionally substituted with R⁶) selected fromC₁₋₆ alkyl, aryl, C₁₋₆ alkyl-aryl, heteroaryl, C₁₋₆ alkyl-heteroaryl,cycloalkyl, C₁₋₆ alkyl-cycloalkyl, heterocycloalkyl or C₁₋₆alkyl-heterocycloalkyl; R⁶ is a group selected from N(R⁷)₂, NR⁷COR⁷,NR⁷CON(R⁷)₂, NR⁷CO₂R⁸, NR⁷SO₂R⁸, OR⁷, COR⁷, CO₂R⁴, CON(R⁷)₂, S(O)₀₋₂R⁸or SO₂N(R⁷)₂; R⁷ is H or a group selected from C₁₋₆ alkyl, aryl, C₁₋₆alkyl-aryl, heteroaryl, C₁₋₆ alkyl-heteroaryl, cycloalkyl, C₁₋₆alkyl-cycloalkyl, heterocycloalkyl or C₁₋₆ alkyl-heterocycloalkyl,wherein said group is optionally substituted with R⁸, COR⁸, SO₀₋₂R⁸,CO₂R⁸, OR⁸, CONR⁴R⁸, NR⁴R⁸ or SO₂NR⁴R⁸ and for each case of N(R⁷)₂ theR⁷ groups are the same or different or N(R⁷)₂ is heterocycloalkyloptionally substituted with R⁸, COR⁸, S(O)₀₋₂R⁸, CO₂R⁸, OR⁸, CONR⁴R⁸,NR⁴R⁸ or SO₂NR⁴R⁸; and R⁸ is C₁₋₆ alkyl, aryl, C₁₋₆ alkyl-aryl,heteroaryl or C₁₋₆ alkyl-heteroaryl; or a salt, solvate, hydrate,N-oxide, protected amino, protected carboxy or protected hydroxamic acidderivative thereof; (b) a compound of formula (I)(B)₂N—X—(CH₂)_(m)-W-(CR¹R²)_(n)—COY  (I) wherein n=0or 1; m=0 or 1; withthe proviso that m and n are not both zero; X is S(O)₁₋₂; Y is OH; W isaryl or heteroaryl; R¹ is H, OR⁷ or a group (optionally substituted withR³) selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, C₁₋₆alkyl-aryl, heteroaryl, C₁₋₆ alkyl-heteroaryl, cycloalkyl, C₁₋₆alkyl-cycloalkyl, heterocycloalkyl or C₁₋₆ alkyl-heterocycloalkyl; andR² is H or C₁₋₆ alkyl; or CR¹R² is cycloalkyl or heterocycloalkyloptionally substituted with R³ or a group (optionally substituted withR³) selected from C₁₋₆ alkyl, aryl, C₁₋₆ alkyl-aryl, heteroaryl or C₁₋₆alkyl-heteroaryl; R³ is OR⁷, COR⁷, CO₂R⁸, CON(R⁷)₂, N(R⁷)₂, NR⁷COR⁷,NR⁷CON(R⁷)₂, NR⁷CO₂R⁸, NR⁷SO₂R⁸, S(O)₀₋₂R⁸, SO₂N(R⁷)₂ or cycloimidyl(optionally substituted with R⁴); R⁴ is C₁₋₆ alkyl; B is H or a group(optionally substituted with R⁵ or R⁶) selected from C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, C₁₋₆ alkyl-aryl, heteroaryl, C₁₋₆alkyl-heteroaryl, cycloalkyl, C₁₋₆ alkyl-cycloalkyl, heterocycloalkyl,C₁₋₆ alkyl-heterocycloalkyl, cycloalkenyl, or heterocycloalkenyl; andeach instance of B may be the same or different; or B-N-B isheterocycloalkyl optionally substituted with R⁵, R⁶, ═O or ═NOR⁵; R⁵ isa group (optionally substituted with R⁶) selected from C₁₋₆ alkyl, aryl,C₁₋₆ alkyl-aryl, heteroaryl, C₁₋₆ alkyl-heteroaryl, cycloalkyl, C₁₋₆alkyl-cycloalkyl, heterocycloalkyl or C₁₋₆ alkyl-heterocycloalkyl; R⁶ isa group selected from N(R⁷)₂, NR⁷COR⁷, NR⁷CON(R⁷)₂, NR⁷CO₂R⁸, NR⁷SO₂R⁸,OR⁷, COR⁷, CO₂R⁴, CON(R⁷)₂, S(O)₀₋₂R⁸ or SO₂N(R⁷)₂; R⁷ is H or a groupselected from C₁₋₆ alkyl, aryl, C₁₋₆ alkyl-aryl, heteroaryl, C₁₋₆alkyl-heteroaryl, cycloalkyl, C₁₋₆ alkyl-cycloalkyl, heterocycloalkyl orC₁₋₆ alkyl-heterocycloalkyl, wherein said group is optionallysubstituted with R⁸, COR⁸, SO₀₋₂R⁸, CO₂R⁸, OR⁸, CONR⁴R⁸, NR⁴R⁸ orSO₂NR⁴R⁸ and for each case of N(R⁷)₂ the R⁷ groups are the same ordifferent or N(R⁷)₂ is heterocycloalkyl optionally substituted with R⁸,COR⁸, S(O)₀₋₂R⁸, CO₂R⁸, OR⁸, CONR⁴R⁸, NR⁴R⁸ or SO₂NR⁴R⁸; and R⁸ is C₁₋₆alkyl, aryl, C₁₋₆ alkyl-aryl, heteroaryl or C₁₋₆ alkyl-heteroaryl; or asalt, solvate, hydrate, N-oxide, protected amino, protected carboxy orprotected hydroxamic acid derivative thereof; and (c) a compound offormula (I) (B)₂N—X—(CH₂)_(m)-W-(CR¹R²)_(n)—COY  (I) wherein n=0 or 1;m=0 or 1; X is S(O)₁₋₂; Y is NHOH; W is aryl or heteroaryl; R¹ is H, OR⁷or a group (optionally substituted with R³) selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, C₁₋₆ alkyl-aryl, heteroaryl, C₁₋₆alkyl-heteroaryl, cycloalkyl, C₁₋₆ alkyl-cycloalkyl, heterocycloalkyl orC₁₋₆ alkyl-heterocycloalkyl; and R² is H or C₁₋₆ alkyl; or CR¹R² iscycloalkyl or heterocycloalkyl optionally substituted with R³ or a group(optionally substituted with R³) selected from C₁₋₆ alkyl, aryl, C₁₋₆alkyl-aryl, heteroaryl or C₁₋₆ alkyl-heteroaryl; R³ is OR⁷, COR⁷, CO₂R⁸,CON(R⁷)₂, N(R⁷)₂, NR⁷COR⁷, NR⁷CON(R⁷)₂, NR⁷CO₂R⁸, NR⁷SO₂R⁸, S(O)₀₋₂R⁸,SO₂N(R⁷)₂ or cycloimidyl (optionally substituted with R⁴); R⁴ is C₁₋₆alkyl; B is H or a group (optionally substituted with R⁵ or R⁶) selectedfrom C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, C₁₋₆ alkyl-aryl,heteroaryl, C₁₋₆ alkyl-heteroaryl, cycloalkyl, C₁₋₆ alkyl-cycloalkyl,heterocycloalkyl, C₁₋₆ alkyl-heterocycloalkyl, cycloalkenyl, orheterocycloalkenyl; and each instance of B may be the same or different;cycloalkyl, C₁₋₆ alkyl-cycloalkyl, heterocycloalkyl, C₁₋₆alkyl-heterocycloalkyl, cycloalkenyl, or heterocycloalkenyl; and eachinstance of B may be the same or different; or B-N-B is heterocycloalkyloptionally substituted with R⁵, R⁶, ═O or ═NOR⁵; R⁵ is a group(optionally substituted with R⁶) selected from C₁₋₆ alkyl, aryl, C₁₋₆alkyl-aryl, heteroaryl, C₁₋₆ alkyl-heteroaryl, cycloalkyl, C₁₋₆alkyl-cycloalkyl, heterocycloalkyl or C₁₋₆ alkyl-heterocycloalkyl; R⁶ isa group selected from N(R⁷)₂, NR⁷COR⁷, NR⁷CON(R⁷)₂, NR⁷CO₂R⁸, NR⁷SO₂R⁸,OR⁷, COR⁷, CO₂R⁴, CON(R⁷)₂, S(O)₀₋₂R⁸ or SO₂N(R⁷)₂; R⁷ is H or a groupselected from C₁₋₆ alkyl, aryl, C₁₋₆ alkyl-aryl, heteroaryl, C₁₋₆alkyl-heteroaryl, cycloalkyl, C₁₋₆ alkyl-cycloalkyl, heterocycloalkyl orC₁₋₆ alkyl-heterocycloalkyl, wherein said group is optionallysubstituted with R⁸, COR⁸, SO₀₋₂R⁸, CO₂R⁸, OR⁸, CONR⁴R⁸, NR⁴R⁸ orSO₂NR⁴R⁸ and for each case of N(R⁷)₂ the R⁷ groups are the same ordifferent or N(R⁷)₂ is heterocycloalkyl optionally substituted with R⁸,COR⁸, S(O)₀₋₂R⁸, CO₂R⁸, OR⁸, CONR⁴R⁸, NR⁴R⁸ or SO₂NR⁴R⁸; and R⁸ is C₁₋₆alkyl, aryl, C₁₋₆ alkyl-aryl, heteroaryl or C₁₋₆ alkyl-heteroaryl; or asalt, solvate, hydrate, N-oxide, protected amino, protected carboxy orprotected hydroxamic acid derivative thereof.
 37. The method accordingto claim 36, wherein the condition is selected from the group consistingof cancer, inflammation and inflammatory diseases, tissue degeneration,periodontal disease, ophthalmological disease, dermatological disorders,fever, cardiovascular effects, haemorrhage, coagulation and acute phaseresponse, cachexia, anorexia, acute infection, HIV infection, shockstates, graft versus host reactions, autoimmune disease, reperfusioninjury, meningitis, migraine and aspirin-independent anti-thrombosis.38. The method according to claim 36, wherein the condition is selectedfrom the group consisting of tumour growth, angiogenesis, tumourinvasion and spread, metastasis, malignant ascites and malignant pleuraleffusion.
 39. The method according to claim 36, wherein the condition isselected from the group consisting of cerebral ischaemia, ischaemicheart disease, rheumatoid arthritis, osteoarthritis, osteoporosis,asthma, multiple sclerosis, neurodegeneration, Alzheimer's,atherosclerosis, stroke and vasculitis.
 40. The method according toclaim 36, wherein the condition is selected from the group consisting ofCrohn's disease, ulcerative colitis, corneal ulceration, retinopathy,surgical wound healing, psoriasis, atopic dermatitis, chronic ulcers,epidermolysis bullosa, periodontitis, gingivitis, rhinitis, allergicconjunctivitis, eczema, anaphylaxis, restenosis, congestive heartfailure, endometriosis, atherosclerosis, endosclerosis, pelvicinflammatory disease (PID), cancer-induced bone resorption, age-relatedmacular degeneration, lung disease, cystic fibrosis adult respiratorydistress syndrome (ARDS), emphysema, bronchitis obliterans-organisingpneumonia (BOOP), idiopathic pulmonary fibrosis (PIF), diffuse alveolardamage, pulmonary Langerhan's cell granulamatosis, pulmonarylymphangioleiomyomatosis, (LAM) and chronic obstructive pulmonarydisease (COPD).